Container assembly for use with planetary mixer

ABSTRACT

The present disclosure relates to a container assembly for use in a planetary mixer, which may comprise a jar with an inner wall, an adapter in contact with the inner wall of the jar, a metered-dosage dispenser having a tubular body, and a lid attachable to an rim of the jar, wherein the adapter, if included, may be configured to clamp to the metered-dosage dispenser, if included, and the adapter, if included, may be further configured to keep the metered-dosage dispenser away from the inner wall of the jar, wherein at least a portion of the metered-dosage dispenser, if included, may be configured to allow visibility of at least some contents inside the body of the metered-dosage dispenser from outside the body of the metered-dosage dispenser, and wherein the body of the metered-dosage dispenser, if included, may have a height-to-base ratio (HBR) between 0.75 and 1.5 at half volume.

CROSS-REFERENCE TO RELATED APPLICATION

This is a continuation of U.S. patent application Ser. No. 15/809,636,filed Nov. 10, 2017, which claims the benefit of U.S. Provisional PatentApplication No. 62/420,426 filed on Nov. 10, 2016, the disclosures ofwhich, including the specification, drawings, and claim, are expresslyincorporated herein by reference in their entireties.

TECHNICAL FIELD

The present disclosure generally relates to the field of compoundingpharmaceutical compositions and, more specifically, to compoundedpharmaceutical compositions having improved quality properties as wellas to systems and methods for making same.

BACKGROUND

Medical facilities, licensed pharmacist or physicians may produceindividual pharmaceutical compositions by blending together variousingredients, such as one or more active pharmaceutical ingredient (API)and pharmaceutically acceptable excipients, diluent or solvents, tocreate a medicine product tailored to the needs of an individualpatient. Such activities are commonly referred as pharmaceuticalcompounding. Practically speaking, in the context of pharmacycompounding, the pharmacist will typically prepare such product tailoredto the needs of an individual patient based on a medical prescription.

Pharmaceutical compounding involves blending of the compositioningredients, which is typically performed using manual mixing, forexample, using a pestle and mortar. However, manually mixing ingredientscan be time-consuming and is often prone to cross-contamination frompoorly decontaminated or sterilized equipment used for the mixing. Alongwith the contamination risk, there is also the problem that performingmanual mixing often results in products that face repeatability and/orquality challenges. In other words, it is often difficult to obtaincompositions having consistent concentrations of API from onecomposition to another and/or consistent homogeneous API concentrationwithin one preparation per se. This may result in substantialqualitative differences during manufacture of the same recipe, which atminimum can have an effect on the effectiveness of the recipe.

In this regard, various practical devices have been previously suggestedto overcome the above deficiencies of compounding pharmaceuticalcompositions using manual mixing.

U.S. 2012/0269029 (Konietzko) describes a program-controlled mixer,which includes a control unit, a motor-driven mixing unit with a blademixing tool, which engages into a mixing vessel, and a lift unit. Thelift unit produces an axial relative motion between the blade mixingtool and the mixing vessel, to move the blade mixing tool in the mixingvessel between an upper end position and a lower one, preferably at aconstant lifting speed.

A deficiency associated with many mixing devices is that they ofteninvolve mixing using blades that contact the mixture causing highshearing forces, which can generate so much heat during mixing so as todegrade thermally labile API.

Additionally or alternatively, many mixing devices often entrain airinto the composition being mixed. The entrained air forms air bubbles inthe composition modifying thereafter the specific gravity of thepharmaceutical composition. Since the specific gravity is the ratio ofthe density of the composition to the density of a reference substance;equivalently, it is the ratio of the mass of the composition to the massof a reference substance for the same given volume. Variations inspecific gravity of a composition can be detrimental in that suchvariations alters the aforementioned ratio and, accordingly, alters theAPI weight content which is filled in a pharmaceutical container for agiven volume of composition filled in. This is particularly critical forpharmaceutical dispensing devices dispensing measured doses which needto dispense consistent amounts of API for a given volume from one deviceto another one, and from one dispensed volume to the next in the samedispensing device.

In other cases, the entrained air must be removed in order to eliminatethe air bubbles from the pharmaceutical composition and thereby improvethe appearance of the pharmaceutical composition. For instance, in theproduction of either translucent or transparent pharmaceuticalcompositions, it is mandatory to remove the air bubbles since thesewould otherwise negatively affect the translucency or transparency ofthe pharmaceutical compositions by imparting opacity zones thereto.However, such de-aeration is time consuming, lowers throughput andgenerally requires additional vacuum configurations, which can becumbersome and increase overall manufacturing costs.

Additionally or alternatively, many mixing devices often require mixingin device-specific mixing containers, which thus requires an additionalstep of decanting the pharmaceutical mixture into a dispensing devicecontainer, thereby increasing the risk of material loss during thedecanting procedure. Device-specific containers also limit the volumeand/or mass of materials that can be mixed to die specifications of suchcontainers, which is not always ideal from a practical perspective.Device-specific containers also require implementing strictcleaning/sterilization procedures to avoid cross-contamination risk whenone wishes to reuse the same mixing containers, which can be cumbersomeand time-consuming. Otherwise, operation costs and waste are increasedwhen container are used and are discarded after each mixing procedure,i.e., when used as single-use mixing containers.

SUMMARY

This Summary is provided to introduce a selection of concepts in asimplified form that are further described below in the DetailedDescription. This Summary is not intended to identify key aspects oressential aspects of the claimed subject matter.

There is a need to provide improved compounded pharmaceuticalcomposition having improved quality properties as well as devices andmethods for making same, which alleviate at least in part thedeficiencies of the existing devices and methods for making compoundedpharmaceutical compositions.

In one embodiment, the present disclosure aims to at least address howto reduce qualitative differences during manufacturing of compoundedpharmaceutical composition mixtures, and/or increase productivity,and/or improve effectiveness of compounded pharmaceutical compositionmixtures.

In one broad aspect, the present disclosure relates to a compositioncomprising an active pharmaceutical ingredient (API) dispersed in apharmaceutically acceptable excipient, carrier or diluent, thecomposition exhibiting a concentration gradient of the API with ≤6%, or≤5%, or ≤4%, or ≤3%, or ≤2%, or ≤1%, or about 0% relative standarddeviation (RSD) when measured by high-performance liquid chromatography(HPLC), wherein the concentration is that of at least top, middle andbottom layers of die composition within the container, and wherein thecomposition is personalized for a patient.

In another broad aspect, the present disclosure relates to a compositioncomprising an active pharmaceutical ingredient (API) dispersed in apharmaceutically acceptable excipient, carrier or diluent, thecomposition exhibiting a concentration gradient of the API with ≤6%, or≤5%, or ≤4%, or ≤3%, or ≤2%, or ≤1%, or about 0% relative standarddeviation (RSD) when measured by high-performance liquid chromatography(HPLC), wherein the concentration is that of at least top, middle andbottom layers of the composition within the container, and wherein thecomposition is personalized for a patient, the composition having aspecific gravity which is within 20% of corresponding specific gravityof the pharmaceutically acceptable excipient, diluent or carrier inabsence of the API.

In yet another aspect, the present disclosure relates to a trochecomprising an active pharmaceutical ingredient (API) dispersed in apharmaceutically acceptable excipient, carrier or diluent, wherein theAPI is thermolabile at a temperature above 60° C., and the trocheincludes less than 1% degradation products of the API, wherein thetroche is personalized for a patient

In yet another aspect, the present disclosure relates to a compoundingmethod, comprising: providing a container including therein apharmaceutically acceptable excipient, carrier or diluent, and an activepharmaceutical ingredient (API); subjecting the container tosuperimposed revolution and rotation movements to disperse thepharmaceutically acceptable excipient, carrier or diluent, and the APIand produce a composition exhibiting a concentration gradient of the APIwith ≤6%, or ≤5%, or ≤4%, or ≤3%, or ≤2%, or ≤1%, or about 0% relativestandard deviation (RSD) when measured by high-performance liquidchromatography (HPLC), wherein the concentration is that of at leasttop, middle and bottom layers of the composition within the container,and wherein the composition is personalized for a patient.

In yet another aspect, the present disclosure relates to a compoundingmethod, comprising: providing a container including therein apharmaceutically acceptable excipient, carrier or diluent having a firstspecific gravity, and an active pharmaceutical ingredient (API); andsubjecting the container to superimposed revolution and rotationmovements to disperse the pharmaceutically acceptable excipient, carrieror diluent, and the API and produce a composition having a secondspecific gravity and exhibiting a concentration gradient of the API with≤6%, or ≤5%, or ≤4%, or ≤3%, or ≤2%, or ≤1%, or about 0% relativestandard deviation (RSD) when measured by high-performance liquidchromatography (HPLC), wherein die concentration is that of at leasttop, middle and bottom layers of the composition within the container,and wherein the composition is personalized for a patient, wherein thesecond specific gravity is within 50%, or 40%, or 30%, or 20%, or 10%,of the first specific gravity without introducing air into thecomposition.

In yet another aspect, the present disclosure relates to a compoundingmethod, comprising: providing a container including therein gelatin gumbase particles; subjecting the container to first superimposedrevolution and rotation movements to disperse the particles and producea melt composition; adding an active pharmaceutical ingredient (API)into the melt to obtain an API-containing melt; subjecting the containercomprising the API-containing melt to second superimposed revolution androtation movements to disperse the API-containing melt and obtain adispersed melt composition; and cooling the dispersed melt compositionto obtain a dispersed solid composition, wherein the dispersed solidcomposition is personalized for a patient.

In yet another aspect, the present disclosure relates to a compoundingmethod, comprising: providing a container including therein particles ofa pharmaceutically acceptable excipient, pharmaceutically acceptablecarrier, or an active pharmaceutical ingredient (API), wherein theparticles have a starting D₅₀; subjecting the container to firstsuperimposed revolution and rotation movements in presence of grindingbeads to produce a milled composition including particles having amilled D₅₀, wherein the starting D₅₀ to milled D₅₀ represent a ratio ofat least 2.5, incorporating into the milled composition at least one ofa pharmaceutically acceptable excipient, pharmaceutically acceptablecarrier, or API and removing the grinding media from the containerbefore or after said incorporating, and subjecting the container tosecond superimposed revolution and rotation movements to obtain acomposition.

In one embodiment, any one of the steps of the herein described methodis performed in a pharmacy setting.

In another embodiment, any one of the steps of the herein describedmethod is performed under the supervision of a licensed pharmacist.

In another embodiment, any one of the steps of the herein describedmethod is performed by a licensed pharmacist or a licensed physician.

In one embodiment, the composition can be any one of a cream, ointment,lotion, emulsion, gel, suspension, powder, liquid solution, colloidaldispersion, troche or syrup.

In one embodiment, the composition of the present disclosure is acomposition which is personalized for a patient.

For the purpose of the present disclosure, the expressions “compoundedpharmaceutical composition” and “composition personalized for a patient”are used interchangeably and refer in particular to those singlecompositions which are assembled in a medical facility, or by a licensedpharmacy (as opposed to those compositions made in batch in apharmaceutical industrial plant) where a pharmacist combines, mutes, oralters ingredients in response to a doctor's prescription to create amedicine tailored to the medical needs of an individual patient. Inother words, the type and/or concentration of at least one of the API,the excipient, diluent or carrier is customized to create a compositiontailored to the medical needs of the patient.

Compounding may, thus, be used in a variety of situations where apatient cannot be treated with a standard, commercially available, FDA-(or other regulatory body) approved medicine.

For example, a patient might be allergic to the kind of dye used in acommercially available medication. In this case, the compoundingpersonnel would formulate the medication without the dye or with anotherdye. Or, sometimes elderly patients or children who cannot swallowtablets need their medicine in a liquid or suppository form that is notcommercially available. Suspensions possess certain advantages overother dosage forms. Some drugs are insoluble in all acceptable media andmust, therefore, be administered as a tablet, capsule, or as asuspension. Because of their liquid character, suspensions represent anideal dosage form for patients who have difficulty swallowing tablets orcapsules. This factor is of particular importance in administration ofdrugs to children. Suspensions of insoluble drugs may also be usedexternally, often as protective agents.

In addition, disagreeable tastes can be masked by a suspension of thedrug or a derivative of the drug, an example of the latter being thedrug chloramphenicol palmitate. Finally, drugs in suspension arechemically more stable than in solution. This is particularly importantwith certain antibiotics and the pharmacist is often called on toprepare such a suspension just prior to the dispensing of thepreparation.

Sometimes, a patient may require a special API dosage and thus, thecompounding personnel will customize the API concentration in thecompounded composition.

In other cases, a patient may be allergic to the API in the commerciallyavailable medication and the compounding personnel will thus customizethe composition by replacing the API with another one, hypoallergenicfor the patient.

The person of skill will recognize that such are examples of acomposition which is personalized for a patient.

All features of embodiments which are described in this disclosure andare not mutually exclusive can be combined with one another. Elements ofone embodiment can be utilized in the other embodiments without furthermention. Other aspects and features of the present invention will becomeapparent to those ordinarily skilled in the art upon review of thefollowing description of specific embodiments in conjunction with theaccompanying Figures.

BRIEF DESCRIPTION OF FIGURES

A detailed description of specific embodiments is provided herein belowwith reference to the accompanying drawings in which:

FIG. 1 shows a cross section view of a jar including a composition whichis personalized for a patient, where the container is virtuallyseparated in top, middle and bottom sections, each including respectivetop, middle and bottom layers of the composition, in accordance with animplementation of the present invention;

FIG. 2 is a flow diagram of a process to obtain the patient personalizedcomposition of FIG. 1, in accordance with an implementation of thepresent invention;

FIG. 3 is a flow diagram of a variant of the process of FIG. 2 includingoperating superimposed revolution and rotation movements to obtain amelt containing an API, and molding the melt into a solid form of apatient personalized composition, in accordance with an implementationof the present invention;

FIG. 4 is a flow diagram of a variant of the process of FIG. 2 includingoperating superimposed revolution and rotation movements in presence ofgrinding media to reduce particle size distribution (PSD) of at leastone ingredient of a patient personalized composition to a desired targetPSD, in accordance with an implementation of the present invention;

FIG. 5 is a flow diagram of a variant of the process of FIG. 2 includingoperating superimposed revolution and rotation movements to disperse(mix) and de-aerate a patient personalized composition, in accordancewith an implementation of the present invention;

FIG. 6 shows a system for compounding a pharmaceutical composition usingsuperimposed revolution and rotation movements, in accordance with animplementation of the present invention;

FIG. 7 shows a top view of the jar of FIG. 1 for use with the system ofFIG. 6, in accordance with an implementation of die present invention;

FIG. 8 shows a side isometric view of a variant dispensing jar for usewith the system of FIG. 6, in accordance with an implementation of diepresent invention;

FIG. 9 shows a side isometric view of dispensing jars, each having arespective body having a different size from one another, for use withthe system of FIG. 6, in accordance with an implementation of thepresent invention;

FIG. 10A shows a cross-sectional view of jar which contains a specificamount of composition, in accordance with an implementation of thepresent invention;

FIG. 10B shows a cross-sectional view of container placed inside jar,where the container contains the same specific amount of composition asin FIG. 10A, in accordance with an implementation of the presentinvention;

FIG. 11 shows a top isometric view of an adapter for use with acontainer for use with the system of FIG. 6, in accordance with a firstimplementation of the present invention;

FIG. 12 shows a side view of the container of FIG. 8, including detailsof the external threads on die nozzle of the container, in accordancewith an implementation of the present invention;

FIG. 13 shows a top isometric view of a variant of the adapter of FIG.11, in accordance with a second implementation of the present invention;

FIG. 14 shows a cross-sectional view of container secured to an insidesurface of a jar via an adaptor, in accordance with an implementation ofthe present invention;

FIG. 15 shows a top isometric view of a variant of the adapter of FIG.11, in accordance with a third implementation of the present invention;

FIG. 16 shows a top isometric view of containing system which includesthe adaptor of FIG. 15 mounted onto the container of FIG. 8, inaccordance with an implementation of the present invention;

FIG. 17 shows a cross-sectional view of a containing system placedinside a jar, in accordance with an implementation of the presentinvention;

FIG. 18A shows a top view of an adaptor having three prongs for use witha container, in accordance with an implementation of the presentinvention;

FIG. 18B shows a side view of the adaptor of FIG. 18A, in accordancewith an implementation of the present invention;

FIG. 19 shows a top isometric view of adaptor of FIG. 18A in which islocated the container, in accordance with an implementation of thepresent invention;

FIG. 20 show a cross-sectional view of the containing system placedinside a jar, in accordance with an implementation of the presentinvention;

FIG. 21 shows a top isometric view of an adaptor having four prongs foruse with a container, in accordance with an implementation of thepresent invention;

FIG. 22 shows a top isometric view of adaptor with a rubberized exteriorperipheral band 2012, in accordance with an implementation of thepresent invention;

FIG. 23A shows a top isometric view of adaptor with a retention elementon die base of the adaptor, in accordance with an implementation of thepresent invention;

FIG. 23B shows a cross-sectional view of a jar having a retentionelement on the inside surface thereof corresponding to the retentionelement on the adaptor of FIG. 23A, in accordance with an implementationof the present invention;

FIG. 24 shows a cross-sectional view of adaptor of FIG. 18A receivingthe container and located inside jar, which has a heat conductivematerial located in between the prong and the inside surface of the jar,in accordance with an implementation of the present invention;

FIG. 25 shows a cross-sectional view of adaptor of FIG. 18A receivingthe container and located inside a jar, which has a thermally insulatingmaterial located in between the prong and the inside surface of the jar,in accordance with an implementation of the present invention;

FIG. 26 shows a side elevation of insert that may be removablypositioned within the jar, in accordance with an implementation of thepresent invention;

FIG. 27 shows a top view of a jar containing grinding media, inaccordance with an implementation of the present invention;

FIG. 28 represents non-limiting graphs showing the interaction profilesof combined effects on SD percent of progesterone in a compositionprepared using superimposed revolution and rotation movements based onparameters varying revolution, rotation and time, in accordance with animplementation of the present invention;

FIG. 29 represents non-limiting graphs showing leverage plots ofparameters with significant effects with respect to SD of percentprogesterone in a composition prepared using superimposed revolution androtation movements based on parameters varying revolution, rotation andtime, in accordance with an implementation of the present invention;

FIG. 30 represents non-limiting graphs showing implementation of adesirability algorithm for optimization of dispersing (mixing) of theprogesterone composition of FIG. 28 and FIG. 29, where the desirabilityis set such that SD of percentage progesterone is zero and time settingis minimized to the lowest value (i.e., 10 seconds), in accordance withan implementation of the present invention;

FIG. 31 represents non-limiting graphs showing initial particle sizedistribution (PSD) of sodium chloride (A) and the PSD after beingprocessed according to prior art mortar and pestle dispersing (mixing)process (B), when processed using superimposed revolution and rotationmovements in presence of grinding media spheres of 8 mm (C) or cylinders(D), in accordance with an implementation of the present invention;

FIG. 32 represents non-limiting graphs showing initial particle sizedistribution (PSD) of Gabapentin (A) and the PSD after being processedaccording to prior art mortar and pestle dispersing (mixing) process(B), when processed using superimposed revolution and rotation movementsin presence of grinding media spheres of 8 mm (Q or cylinders (D), inaccordance with an implementation of the present invention;

FIG. 33 shows a typical gum base gelatin particle unaltered from diemanufacturers' container (left) and a plurality of these particlescontained in the dispersion container (tight). The block has a maximalextent size of about 1 inch, in accordance with an implementation of thepresent invention;

FIG. 34 shows gum base gelatin particles which have been cut down fromthe initial size present in the manufacturers' container (left) and aplurality of these particles contained in the dispersion container(right). The cut down particles have a size of less than about 0.5 inch,in accordance with an implementation of the present invention;

FIG. 35A-35E shows examples of gum base in the dispersion container thatcompletely melted (35A), partially melted (35B, 35C and 35D), and didnot melt (35E), in accordance with an implementation of the presentinvention;

FIG. 36 represents a non-limiting graph showing melting of gum basegelatin when processed using superimposed revolution and rotationmovements based on parameters of constant time and increasing G Force,in accordance with an implementation of the present invention;

FIG. 37 represents a non-limiting graph showing melting of gum basegelatin when processed using superimposed revolution and rotationmovements based on parameters of constant G force and increasing time,in accordance with an implementation of the present invention;

FIG. 38 represents a non-limiting graph showing melting of gum basegelatin when processed using superimposed revolution and rotationmovements based on parameters of constant G force and time, whileincreasing the mass, in accordance with an implementation of the presentinvention;

FIG. 39 represents a non-limiting graph showing percentage de-aerationof a personalized composition when processed using superimposedrevolution and rotation movements based on parameters of constant timeand variable G force, in accordance with an implementation of thepresent invention;

FIG. 40 represents a non-limiting graph showing percentage de-aerationof a personalized composition when processed using superimposedrevolution and rotation movements based on parameters of constant Gforce and variable time, in accordance with an implementation of thepresent invention;

FIG. 41 represents a non-limiting graph showing particle size (μm) withrespect to D10, D50 and D90 of 23 gram of NaCl when processed usingsuperimposed revolution and rotation movements based on parameters ofconstant G Force in presence of grinding media or when processed withcontrol mortar and pestle, in accordance with an implementation of thepresent invention;

FIG. 42 represents a non-limiting graph showing particle size (μm) withrespect to D10, D50 and D90 of 50 gram of NaCl when processed usingsuperimposed revolution and rotation movements based on parameters ofconstant G Force in presence of grinding media or when processed withcontrol mortar and pestle, in accordance with an implementation of thepresent invention;

FIG. 43 represents a non-limiting graph showing particle size (μm) withrespect to D10, D50 and D90 of 22.9 gram of NaCl when processed usingsuperimposed revolution and rotation movements based on parameters of 60seconds in presence of grinding media or when processed with controlmortar and pestle, in accordance with an implementation of the presentinvention;

FIG. 44 represents a non-limiting graph showing temperature increase(gain in degrees Celsius) when processing NaCl when processed usingsuperimposed revolution and rotation movements based on parameters ofconstant G force and increasing time period in presence of grindingmedia, in accordance with an implementation of the present invention;

FIG. 45 represents a non-limiting graph showing temperature increase(gain in degrees Celsius) when processing NaCl when processed usingsuperimposed revolution and rotation movements based on parameters ofconstant time period and increasing G force in presence of grindingmedia, in accordance with an implementation of the present invention;

In the drawings, embodiments are illustrated by way of example. It is tobe expressly understood that the description and drawings are only forthe purpose of illustrating certain embodiments and are an aid forunderstanding. They are not intended to be a definition of the limits ofthe invention.

DETAILED DESCRIPTION

Illustrative embodiments of the disclosure will now be more particularlydescribed. The same features are denoted m all figures by the samereference signs. While the making and using of various embodiments ofthe present invention are discussed in detail below, it should beappreciated that the present invention provides many applicableinventive concepts that can be embodied in a wide variety of specificcontexts. Specific embodiments discussed herein are merely illustrativeof specific ways to make and use the disclosure and do not delimit thescope of the disclosure.

Composition

A composition of the present disclosure includes one or more ingredientwhich is tailored to medical needs of an individual patient. Thecomposition further includes one or more characteristics which, whencompared to compositions obtained with prevalent compounding methodsthat make use, e.g., of manual mixing, may constitute an improvementfrom a safety and/or quality and/or effectiveness perspective.

In one embodiment, the composition of the present disclosure can be anyone of a cream, ointment, lotion, emulsion, gel, suspension, powder,liquid solution, colloidal dispersion, troche or syrup. For the purposeof the present disclosure, the compounding composition of the presentdescription may be packaged in a metered dose device and/or a unit dosepackage. A metered dose device allows to administrate a dose ofcompounding composition, the dose of compounding composition beingmetered by weight or by volume. In one non-limiting example, the metereddose device is an inhaler comprising a canister, a metering valve and anactuator. The canister encloses the compounding composition, while themetering valve allows a metered dose of the compounding composition tobe dispensed at each actuation of the actuator, the actuator being amouthpiece in this example. In another non-limiting example, the metereddose device comprises a container enclosing the compounding composition,an actuator manually operated, and a metering valve allowing a metereddose of the compounding composition to be dispensed at each actuation ofthe actuator. A unit dose package (also referred as “individualpackage”) allows the compounded composition to be dispensed more safelyand efficiently by enclosing each unit dose in a different recipient. Aunit dose is typically a dose of medication comprising a dose of atleast one compounded composition that is intended to be administrated atonce. The recipients may comprise paper, cardboard, plastic, metaland/or glass materials. In one non-limiting example, the recipients arepaper envelopes. In another non-limiting example, the recipients arereusable boxes. In one non-limiting example, the recipients aresingle-use plastic boxes with a detachable paper lid. The recipients maybe tagged, marked with information, such as a name of a patient, a nameof a medication, a barcode and/or a moment (i.e. a day, a date and/or amoment of the day) at which the unit dose is intended to beadministrated. In one non-limiting example, each recipient is taggedwith a day of the week and a meal: Monday-breakfast, Monday-diner,Tuesday-breakfast, etc. The unit dose package may be provided bymanually packaging the unit doses or by an automated packaging system.

In a first practical implementation, the composition of the presentdisclosure includes at least one active pharmaceutical ingredient (API)dispersed (mixed) in a pharmaceutically acceptable excipient, diluent orcarrier in such a way that the composition has substantially the sameAPI concentration in a top layer, a middle layer and a bottom layer ofthe composition, as measured with high-performance liquid chromatography(HPLC). Such composition will be referred to in this text as being a“substantially homogeneous composition”.

The concept of having substantially the same API concentration in a top,middle and bottom layer of the composition is illustrated in FIG. 1A,which shows a cross-sectional view of a container 102 including apatient personalized composition, where the container 102 is virtuallyseparated in top, middle and bottom sections, each including respectivetop 2, middle 4 and bottom 6 layers of the composition. Theconcentration of the API dispersed (mixed) in the composition is thenmeasured in each of layers 2, 4 and 6 using a suitable technique, suchas HPLC. The standard deviation (SD) between the API concentrations ofthe three layers 2, 4 and 6 for a given composition is then determined.The relative standard deviation (% RSD), which expresses the precisionand repeatability of an assay, is then calculated based on the ratio ofthe standard deviation to the mean.

In a non-limiting embodiment, the composition exhibits a concentrationgradient of the API having ≤3% relative standard deviation (% RSD), or≤2% RSD, or ≤1% RSD, when measured at least at the top 2, middle 4 andbottom 6 layers of the composition using HPLC. In a non-limitingembodiment, the concentration gradient of the API is nil (about 0% RSD),when measured at least at the top 2, middle 4 and bottom 6 layers of thecomposition using HPLC.

In one embodiment, the API can be present in an amount of ≤80 wt. %relative to total weight of the composition. For example, the API can bepresent in an amount selected in the range of 0.05 wt % to 80 wt. %, or0.05 to 70 wt. %, or 0.05 to 60 wt. %, or 0.05 to 50%, or 0.05 to 50 wt.%, or any other desired amount.

In a non-limiting embodiment, the composition includes at least a secondAPI dispersed (mixed) in the pharmaceutically acceptable excipient,carrier or diluent, the second API, and the composition exhibiting aconcentration gradient of the at least second API having ≤6% RSD, or ≤3%RSD, or ≤2% RSD, or ≤1% RSD, when measured at least at the top 2, middle4 and bottom 6 layers of the composition using HPLC. In a non-limitingembodiment, the concentration gradient of the at least a second API isnil (about 0% RSD), when measured at least at the top 2, middle 4 andbottom 6 layers of the composition using HPLC.

In a non-limiting embodiment, the concentration gradient of the at leastsecond API can be approximately the same as the concentration gradientof the first API.

In another non-limiting embodiment, the concentration gradient of the atleast second API is significantly different than the concentrationgradient of the first API.

Different types of pharmaceutical compositions have been prepared by thepresent inventors with the above low % RSD values.

In a second practical implementation, the composition of the presentdisclosure includes an API dispersed (muted) in a pharmaceuticallyacceptable excipient, diluent or carrier in such a way that thecomposition has reduced air entrapment levels.

One practical way of assessing air entrapment levels in the compositionis to measure the specific gravity of the composition before and afterthe dispersion (mixing) procedure and/or of a composition prepared withthe herein described process to a composition prepared with a dispersionprocedure of the prior art, such as mixing with an electronic mortar andpestle.

For example, it has been observed by the present inventors thatcompounding pharmaceutical ingredients using prior art processes such asthe electronic mortar and pestle can incorporate significant amounts ofair into the composition under certain circumstances (i.e., >30%variation in the composition's specific gravity). In such cases, the airentrapped in the composition creates air bubbles which are undesirablefrom a product quality perspective. It is, thus, common in the art tofurther process compositions which have been muted with the electronicmortar and pestle with another device to remove the air bubblesentrapped therein. In such cases, the compounding process can thusinclude the use of at least two devices, the electronic mortar andpestle and another device such as the Unguator™ (Gako InternationalGmbH), to remove entrapped air. The use of two devices can becumbersome, increase operation costs, delays, likelihood ofcross-contamination, material loss (e.g., through decanting from onecontainer suitable for mixing with the electronic mortar and pestle toanother container suitable for the Unguator), and/or other undesirableeffects which will become apparent to the person of skill in view of thepresent disclosure.

In contrast, and as will be further discussed later in this text, theherein described superimposed revolution and rotation movements,typically, will not introduce air during the dispersing (mixing)process, and if the starting composition ingredients (i.e., beforedispersion) initially include air entrapped therein, the hereindescribed superimposed revolution and rotation movements will deaeratethe composition while dispersing (mixing) the ingredients. This can beadvantageous, in particular when the herein described superimposedrevolution and rotation movements is implemented in a single device, aswill be further discussed later in this text.

In this particular implementation, the patient personalized compositionof the present disclosure includes an API dispersed (mixed) in apharmaceutically acceptable excipient, diluent or carrier. Thecomposition has a specific gravity which is within 20%, or within 10%,or within 5%, or within 2%, of the specific gravity of thepharmaceutically acceptable carrier, diluent or excipient in absence ofthe API. Preferably, such composition exhibits a concentration gradientof the API with ≤6% RSD, or ≤3% RSD, or ≤2% RSD, or ≤1% RSD, or RSDbeing nil (about 0%), when measured at least at the top 2, middle 4 andbottom 6 layers of the composition using HPLC, relative standarddeviation (RSD) when measured at least at a top, middle and bottomlayers of the composition by high-performance liquid chromatography(HPLC).

In one embodiment, the composition of the present disclosure includes anAPI dispersed (mixed) in a pharmaceutically acceptable excipient,diluent or carrier, and has a specific gravity which is substantiallyidentical to the specific gravity of the pharmaceutically acceptablecarrier, diluent or excipient without the API.

In a third practical implementation, the composition of the presentdisclosure includes an API which is thermally labile at a temperatureabove 50° C., or above 60° C., or above 80° C. The API is dispersed(mixed) in a pharmaceutically acceptable excipient, diluent or carrier.This composition includes less than 1.0% degradation products of thethermally labile API. The person of ordinary skill will readilyappreciate that the percentage here represents a wt./wt percentagerelative to the total weight of the thermally labile API added into thecomposition before dispersion (mixing).

In one non-limiting embodiment, the amount of degradation products ofthe thermally labile API represents less than 0.75%, 0.5%, 0.1%, 0.05%,or 0.01% wt./wt. percentage relative to the total weight of thethermally labile API added into the composition before dispersion.

For the purpose of the present specification, a thermally labile API isan active pharmaceutical compound that is altered or degrades whenexposed to high temperatures, e.g. above 50° C., or above 60° C., orabove 80° C., or more. Typically, compounding methods that make use ofblades for mixing will generate high temperatures, which can alter ordegrade thermally labile API to a certain extent such that it increasescosts and/or reduces yield of composition having effective APIconcentrations and/or produces unwanted degradation and/or alteration ofthe API, possibly generating by-products. In certain prior artcompounding methods that make use of blades, it can be quite common toobtain dispersed composition having more than 1.5% degradation productsof thermally labile API.

The reader will readily understand that quantification of APIdegradation product levels in the dispersed composition can be performedusing one of a variety of chromatographic or spectroscopic techniquesknown in the art, including HPLC, thin-layer chromatography (TLQ, Highperformance thin layer chromatography (HPTLC), Atomic absorptionspectroscopy (AAS), and the like.

In a fourth practical implementation, the composition of die presentdisclosure is in the form of a molded troche and includes an APIdispersed in a pharmaceutically acceptable excipient, diluent orcarrier. The API is thermolabile at a temperature above 60° C. and thecomposition includes less than 1.0% degradation products of thethermally labile API wt./wt. percentage relative to the total weight ofthe thermally labile API added into the composition before dispersion.

In one non-limiting embodiment, the amount of degradation products ofthe thermally labile API in the troche represents less than 0.75%, 0.5%,0.1%, 0.05%, or 0.01% wt./wt percentage relative to the total weight ofdie thermally labile API added into the composition before dispersion.

In a specific embodiment, the troche is a chewable troche.

In a specific embodiment, the troche includes a gum base gelatin.

The troche can have similar features as chose set forth previously withrespect to the composition, namely a concentration gradient of the APIwith ≤6% RSD, or ≥3% RSD, or ≤2% RSD, or ≤1% RSD, or RSD being nil(about 0%), when measured at least at a top, middle and bottom layers ofthe troche by high-performance liquid chromatography (HPLC)

A troche (also interchangeably referred to in the text as a “lozenge”)is intended to be held in the mouth or pharynx and contains one or moreAPI(s) either dissolved or dispersed in a base. Troches are typicallyused for patients who have difficulty swallowing solid oral dosage forms(for example, paediatric or geriatric patients) as well as for API(s)which should be released slowly to yield a constant amount of drug inthe oral cavity or to coat the throat tissues with the API(s).Commercial lozenges are made by moulding or by compression.

Compression techniques are typically used when manufacturing solidtroches that are intended to slowly dissolve or disintegrate in themouth. Compression is also advisable when incorporating thermolabileAPIs, as there is no excessive heat involved when compressing the trocheingredients.

Moulding techniques are typically used when manufacturing solid, soft orchewable troches and in particular, when one wishes to impart a specificshape to the troche. Moulding techniques usually involve hightemperature processing of the ingredients to obtain a melt, dispersingthe API in the melt to obtain an API-containing melt, and casting thedispersed API-containing melt into a mold having a desired shape, andcooling the API-containing melt into the desired shape. Because of thehigh temperatures (e.g., 90-100° C.) usually involved with moulding,troches made with this technique typically do not include thermolabileAPIs, as thermolabile APIs will usually degrade or convert toby-products in presence of such high temperatures. This in turneffectively limits the nature or concentration of the API that can beincorporated into molded troches to a certain non-thermolabile subset,which may not be practical for certain applications.

As explained later in the present disclosure, the herein describedsuperimposed revolution and rotation movements can be used to obtain amelt and disperse therein a thermolabile API at a temperature which issufficiently low so as to limit the degradation of the thermolabile APIand obtain an API-containing melt which can be molded into a trochehaving less than 1.0%, 0.75%, 0.5%, 0.1%, 0.05%, or 0.01% degradationproducts of the thermally labile API.

Superimposed Revolution and Rotation Movements

A number of devices can be used to obtain the compounded pharmaceuticalcomposition of the present disclosure so long as the device is capableof implementing the superimposed revolution and rotation movements asdescribed herein.

In one non-limiting practical implementation, the herein describedsuperimposed revolution and rotation movements can be performed using aplanetary mixer.

A planetary mixer is capable of performing the herein describedsuperimposed revolution and rotation movements by continually andconcurrently revolving and rotating a container which includes thecomposition ingredients. This dual action eliminates the need for mixingrods, blades or media, or an evacuation device and can dramaticallyreduce processing times relative to other mixing devices that use bladesto mix ingredients. In one embodiment, the mixing time may be no morethan 900 seconds. For example, the herein described superimposedrevolution and rotation movements may be performed for less than 10, 15,20, 25, 30, 35, 40, 45, 50, 55, 60, 75, 100, 120, 150, 180, 240, 300,400, 500, 600, 700, 800, or 900 seconds, as well as any values includedtherein.

Such processing time is significantly reduced when compared to theprocessing time required for compounding processes known in the art forcompounding pharmaceutical compositions, such as the typical mortar andpestle system or devices with mixing blades, which may require anadditional vacuum step to remove air entrapment in the composition.While the processing time in the superimposed revolution and rotationmovements of the present disclosure is thus relatively reduced, theintensity of the processing procedure is sufficiently intense todisperse the ingredients to the point where the resulting mixture issubstantially homogenous and is sufficiently gentle to prevent theinternal temperature of the mixture from reaching or getting close to adegradation temperature threshold of the API.

In one embodiment, the superimposed revolution and rotation movementparameters may induce a maximal G force value of at least 50 g(corresponding to approximately 1490 m/s²). In some cases, thesuperimposed revolution and rotation movement parameters may induce amaximal G force value of less than 500 g, or in the range of 50 g to 400g, or 75 g to 350 g, or any suitable value within these ranges. Inducingsuch a maximal G force in a process by performing the herein describedsuperimposed revolution and rotation movements can be useful forcompounding compositions which are otherwise difficult or cumbersome tocompound using prior art electronic mortar and pestle system or deviceswith mixing blades.

In one embodiment, the superimposed revolution and rotation movementsare operated with operational parameters that may include revolutionspeeds of from at least 400 revolutions per minute (“rpm” or “RPM”). Forexample, a suitable revolution speed can be selected in the range offrom 400 to about 4000 rpm, or from 400 to about 2000 rpm, or anysuitable value within these ranges.

In one embodiment, the superimposed revolution and rotation movementsare operated with operational parameters that may includerevolution:rotation rpm ratios of about 10:4.

In certain embodiments, the revolution rpm, the rotation rpm and themixing time are configurable parameters and their values may beindividually selectable or they may be selectable from pre-determinedcombinations of parameter values. In other embodiments, the ratiobetween rotation rpm and revolution rpm may be a configurable parameterand thus would constrain the revolution rpm for a certain rotation rpmor vice versa. Moreover, the geometric configuration of the planetarymixer (e.g., the eccentricity (distance between the center of rotationand the center of revolution), the dimensions of the container, etc.),combined with the revolution rpm and rotation rpm, results in a certainacceleration (G force, measured in g or m/s²) being felt by the materialin the container. In some embodiments, the desired G force may be inputto the planetary mixer, which could result in selection, by theplanetary mixer, of the revolution rpm and/or the rotation rpm.

In other embodiments, the minimum or maximum G force may be specified,resulting in thresholding of the rotation rpm and/or the revolution rpm,depending on the values entered. In still further embodiments, certainparameters (such as the rotation rpm or the revolution rpm) may bedynamic (i.e., vary over time) and may be input as a function of timefunction so as to follow a pre-determined curve. There may exist stillfurther controllable parameters of superimposed revolution and rotationmovements implemented by a planetary mixer, such as the total weight ofthe container being mixed.

The reader will readily recognize that the herein described processoffers a number of benefits to the compounding industry, in particularwhen this process can be integrated within a single device, namely aplanetary mixer.

Various implementations of the herein described superimposed revolutionand rotation movements will now be described with reference todispersing, milling, melting and de-aerating applications forcompounding pharmaceutical compositions (i.e., patient personalizedcompositions), which can be advantageously performed in a pharmacysetting in a single device, namely a planetary mixer.

While each of these applications is described in the following sectionsas separate variant processes, the reader will readily understand thatthese applications are not mutually exclusives. In other words, morethan one of these applications can be performed during the samesuperimposed revolution and rotation movements implemented in singleplanetary mixer, i.e., ingredients of a patient personalized compositioncan be processed so as to mix and de-aerate; or so as to mix, melt andde-aerate; or so as to mix and grind; or any other combinations thereof.

Mixing Process

FIG. 2 is a flow chart of a general process 100 of preparing acompounded pharmaceutical composition in accordance with an embodimentof the present disclosure.

In the process 100, the superimposed revolution and rotation movementsare implemented in a planetary mixer for preparing a patientpersonalized composition by dispersing an API into a pharmaceuticallyacceptable excipient, diluent or carrier so as to obtain a substantiallyhomogeneous patient personalized composition.

At step 110, the process includes providing the composition ingredientsin a container (also referred to in this text as a “jar”) configured forcontaining the composition ingredients. Typically, the compositioningredients include at least one API and at least one pharmaceuticallyacceptable excipient, diluent or carrier.

At step 120, the process includes obtaining pre-determined ordetermining dispersing parameters which are required to perform asuperimposed revolution and rotation movements on the compositioningredients to obtain a substantially homogeneous dispersed composition.

At step 130, the process then includes dispersing the composition usingthe superimposed revolution and rotation movements at least based on thepre-determined or determined dispersing parameters so as to produce thesubstantially homogeneous dispersed composition.

Melting Process

FIG. 3 is a flow chart of a process variant 100′ of preparing acompounded pharmaceutical composition in accordance with an embodimentof the present disclosure. In this variant, the process 100′ isimplemented in a planetary mixer for preparing a patient personalizedcomposition by reversibly melting pharmaceutically acceptable excipient,diluent or carrier initially in the form of solid or semi-solidparticles, incorporate into the resulting melt an API, dispersing theAPI into the melt, and casting the melt into a desired shape, such as atroche.

The variant 100′ includes at step 210, providing pharmaceuticallyacceptable excipient, diluent or carrier in the form of solid orsemi-solid particles in a container configured for containing theparticles. Optionally, at this step, at least one API is also providedin the container.

In one embodiment, the excipient, diluent or carrier in the form ofsolid or semi-solid particles is a polymeric material which can bereversibly melted. In a particular implementation, excipient, diluent orcarrier in the form of solid or semi-solid particles is a gelatin-basedmaterial.

At step 220, the process includes obtaining pre-determined ordetermining dispersing parameters which are required to perform thesuperimposed revolution and rotation movements on the solid orsemi-solid particles to obtain a more or less viscous melt.

At step 230, the process includes dispersing the solid or semi-solidparticles at least based on the pre-determined or determined parametersto obtain the melt. Without being bound by any theory, it is believedthat the superimposed revolution and rotation movements can melt thesolid or semi-solid particles through impact of the particles againsteach other and/or against the container walls, thus generating kineticenergy, without requiring the addition of external heat. This processadvantageously can melt the material at a temperature which is below theTg or Tm of the solid or semi-solid particles.

In one embodiment, the at least one API is not incorporated into thecontainer at step 210. In such embodiment, the solid or semi-solidparticles are thus melted in step 230 in the absence of an API. In suchembodiment, it is thus necessary to incorporate at least one API at onepoint to obtain the compounded pharmaceutical composition. This isachieved with optional step 240, in which an API is added to the meltobtained in step 230 so as to obtain an API-containing melt. In FIG. 3,step 240 is therefore labelled as being optional as it may be discardedin case at least one API was incorporated into the container at step 210and no further API is added to the composition.

At step 250, the process includes obtaining pre-determined ordetermining second dispersing parameters which are required to performsecond superimposed revolution and rotation movements on theAPI-containing melt to obtain a substantially homogeneous dispersedcomposition.

At step 260, the process then includes dispersing the API-containingmelt at least based on the pre-determined or determined seconddispersing parameters to so as to produce a substantially homogeneousdispersed composition.

At step 270, the process then includes incorporating the dispersedcomposition into a mold having a desired shape and causing theincorporated dispersed composition to solidify into the mold shape.

This process 100′ thus affords the reversible melt of pharmaceuticallyacceptable excipients, carriers or diluents which can be useful, forexample, when making compositions which require pouring into some sortof mold to impart a shape thereto, for instance when making compoundedpharmaceutical compositions in the form of troches, suppositories orthroat lozenges. Advantageously, the melt can be obtained with theherein described dispersing process at temperatures below the typicalmolten transition temperature of the ingredients being dispersed suchthat it may enable the production of solid dispersion systems fromthermally incompatible materials. In other words, such composition canadvantageously incorporate thermally labile API which are typically notfound or are found in limited concentration in troches.

In the prior art, such shaped compounded pharmaceutical compositions aretypically made by first thermally treating a suitable pharmaceuticallyacceptable excipients, carriers or diluents in solid form for asufficient extent of time so as to obtain a melt, adding the desired API(or mixture thereof), dispersing the API into the melt to obtain amixture, and pouring the mixture into the mold so as to obtain thedesired shaped compounded pharmaceutical composition. It will be notedthat, typically, API which are incorporated into such meltedpharmaceutically acceptable excipients, carriers or diluents are morethermally resistant so as to be able to beat the higher temperaturesinvolved with melting the carrier, excipient or diluent. This, in turn,can limit the nature of the API that can be incorporated into such meltsor requires higher amounts of API to take into account the expected APIthermal degradation.

Milling Process

FIG. 4 is a flow chart of a process variant 100″ of preparing acompounded pharmaceutical composition in accordance with an embodimentof the present disclosure. In this variant, the process 100″ isimplemented in a planetary muter for preparing a patient personalizedcomposition which includes a step of reducing the particle sizedistribution (PSD) of at least one of the ingredients in the patientpersonalized composition. Reducing the PSD of one of the ingredients canbe useful in reducing the gritty feeling of the resulted compoundedcomposition, such as for example but not being limited to the case of atopical cream, ointment or gel.

The process 100″ includes at step 310, providing a container includingat least one patient personalized composition ingredient such as one ofan API, a pharmaceutically acceptable excipient, diluent or carrier inthe form of particles where the container is configured for containingthe particles.

At step 320, the process includes obtaining pre-determined ordetermining dispersing parameters which are required to performsuperimposed revolution and rotation movements on the particles toreduce the PSD to a desired target PSD. Advantageously, thepre-determined or determined dispersing parameters are selected so as toensure that any heat generation which could be caused during thedispersing step through the impact of particles and/or grinding mediaagainst each other and/or against the container inner walls does notreach a degradation temperature of the API.

At step 330, the process includes adding grinding media to thecontainer. It will be apparent to the reader that steps 320 and 330 canoccur in any sequence and are not limited to a serial sequence. In otherwords, the step 330 can occur before, during or after step 320.

At step 340, the process includes dispersing the grinding media and theparticles at least based on the pre-determined or determined parametersto reduce the PSD to the desired target PSD.

At step 350, the grinding media is separated from the dispersedcomposition. This can be achieved either by removing from the container,the grinding media or the dispersed composition.

When step 310 does not include the addition of an API and/or when thecompounding prescription recipe requires addition of an API after thedispersing step 340, the process includes a step 360. It will beapparent that this step is optional as the API can be incorporated atstep 310. At step 360, an API is incorporated into the dispersedcomposition obtained after step 350.

At optional step 370, the process includes obtaining pre-determined ordetermining second dispersing parameters which are required to performsuperimposed revolution and rotation movements on the dispersedcomposition obtained after step 360 so as to obtain a substantiallyhomogeneous dispersed composition.

At optional step 380, the process includes dispersing the compositionusing the superimposed revolution and rotation movements at least basedon the pre-determined or determined second dispersing parameters so asto produce the substantially homogeneous dispersed composition.

It will apparent that in a variant, the superimposed revolution androtation movements in presence of grinding media are performed on theAPI in presence of the pharmaceutically acceptable excipient, diluent orcarrier.

In another variant, the superimposed revolution and rotation movementsin presence of grinding media are performed on the API in absence of thepharmaceutically acceptable excipient, diluent or carrier.

When performing the process in presence of grinding media, the size ofthe particles to grind, the size of the grinding media used to grind,and the size of the resulting parades can be selected such that, forexample:

0.004<MS(SP)/MS(B)≤0.12

0.0025<MS(FP)/MS(SP)≤0.25

-   -   where MS(SP) represents the mean size diameter of the particles        before grinding (starting particles), MS(FP) represents the mean        size diameter of the particles after grinding (final particles),        and MS(B) is the mean size diameter of die grinding beads.

The grinding media may include balls (spheres) or pellets (cylinders)made of, for example, but not limited to, hardened steel, stainlesssteel, tungsten carbide, agate, sintered aluminium oxide, siliconnitride or zirconium oxide.

De-Aerating Process

FIG. 5 is a flow chart of a process variant 100′″ of preparing acompounded pharmaceutical composition in accordance with an embodimentof the present disclosure.

In this variant, the process 100′″ is implemented in a planetary mixerfor preparing a patient personalized composition by dispersing an APIinto a pharmaceutically acceptable excipient, diluent or carrier in suchmanner as to minimize air entrapment into the dispersed composition orto remove any air which was present in the composition beforedispersion. This can be useful in controlling the composition's specificgravity and/or reducing incorporation of air bubbles in the resultingpatient personalized composition, such as for example but not limited totopical creams, ointments or gels.

The process 100′″ includes at step 410, providing patient personalizedcomposition ingredients such as an API, a pharmaceutically acceptableexcipient, diluent or carrier in a container configured for receivingthese ingredients.

At step 420, the process includes obtaining pre-determined ordetermining dispersing parameters which are required to performsuperimposed revolution and rotation movements on the personalizedcomposition ingredients to disperse same while reducing or maintaining atarget content of incorporated air in the composition.

At step 430, the process includes dispersing the ingredients using thesuperimposed revolution and rotation movements at least based on thepre-determined or determined parameters to disperse same while reducingor maintaining a target content of incorporated air in the composition.

Equipment and Processes for Industrial Applicability of the Invention

The herein described bladeless dispersion pattern process may beperformed in a single device, notably in a planetary mixer.

Commercially available planetary mixers, such as the MAZERUSTAR mixerKK-300SS, ICK-400W or KK-1000W from Kurabo Industries, Ltd. of Osaka,Japan or the THINKY MIXER AR-100, ARE-310, ARE-400TWIN, ARE-500,ARV-50LED, ARV-310/31 OLED, ARV-930-TWIN, ARV-5000, ARV-3000TWIN, andARV-10kTWIN from Thinky Corporation of Tokyo, Japan, and the like, canbe used for this purpose.

A planetary mixer typically includes a jar arranged eccentrically on aso-called sun wheel, at a certain distance from the center. The jar isconfigured for receiving a container which contains the ingredientsbeing processed. The planetary mixer is configured to impart arevolution movement to the sun wheel and a rotational movement to thejar, where the revolution movement is in an opposite direction to thatone of the rotation such that the ingredients contained in the containerare subjected to a pattern of motion throughout space, which includessuperimposed revolution and rotation movements. Advantageously, thispattern of motion throughout space does not involve any blades, i.e., itis a bladeless dispersion pattern of motion throughout space. Whengrinding media is added to the container, the grinding media is alsosubjected to these superimposed movements, where the difference inspeeds between the grinding media and the container produces aninteraction between frictional and impact forces, which releases highdynamic energies causing size reduction of the materials in thecontainer.

In certain embodiments, the container receiving the ingredient isadapted to receive on a top end thereof, a dispensing system elementsuch as a pump, a spray nozzle, applicator cap, and the like. It will beappreciated that the dispensing system element can further be adaptedfor dispensing metered doses as described, e.g., in U.S. 2014/0221943filed Feb. 4, 2014 and PCT/CA2016/050179, filed Feb. 23, 2016. Thisimplementation effectively avoids or eliminates decanting steps, thus,minimizing the risk of material loss. This implementation also reducestime required for cleaning the container after a compounding procedure,which is typically required to avoid cross-contamination risks thatexist when using the same container for dispersion of various compoundedpharmaceutical compositions. The reader will appreciate that whenperforming the milling step, the grinding media is preferably removedfrom due container before the latter receives the dispensing systemelement at the top end thereof.

Such features are also advantageous to the compounding industry and arebelieved to address an unmet need in this industry.

FIG. 6 generally shows a planetary mixing system 10 which includes aplanetary mixing apparatus 100 configured to effect the herein describedsuperimposed revolution and rotation movements through rotation andrevolution of a jar 102 placed in a jar holder 104.

The system 10 includes a lid 106 that attaches onto a mouth 108 of thejar 102. The lid 106 may be a screw-on lid as shown, or it may be asnap-on lid, for example. The jar 102 and the lid 106 may be made ofhigh density polyethylene (HDPE) or polypropylene, for example.

The jar 102 may have different interior and exterior dimensions. Withreference to the elevated cross-sectional view in FIG. 1, the jar 102may have an inside diameter 202, 204, 206 that changes from the top ofthe jar 102 to the bottom of the jar 102. For example, the insidediameter 202 at the top of the jar 102 may be smaller than the insidediameter 206 at the bottom of the jar 102. This gradient can be achievedin two or more sections or as a gradual taper. In the illustratedembodiment, the jar 102 has three sections 212, 214, 216, with the topsection 212 having the smallest inside diameter 202, the bottom section216 having the largest inside diameter 206 and die middle section 214whose inside diameter 204 is somewhere in between. Example dimensionsfor the top, middle and bottom inside diameters, not to be consideredlimiting, are 65 to 70 mm, 65 to 70 mm and 65 to 70 mm, respectively.Alternatively, one can consider that the top inside diameter 202 isbetween 90 and 99.9 percent of the middle inside diameter 204, and themiddle inside diameter 204 is between 90 and 99.9 percent of the insidediameter 206. Also, there are multiple height dimensions possible forthe jar 102. For example, the height dimension of the jar 102 (measureexternally) could be in the range from 85 mm to 120 mm.

The outside of the jar 102 may be configured to be received in the jarholder 104. In particular, the jar holder 104 may include a plurality ofcircumferentially spaced projections 104A. Correspondingly, and as shownwith additional reference to FIG. 7, the jar 102 may, accordingly,include a plurality of circumferentially spaced notches 302 that receivethe projections 104A, so as to prevent free-spinning of the jar 102within the jar holder 104. As a result, rotation of the jar 102 willonly occur when the jar 104 holder itself rotates. Other rotationalstoppage mechanisms may be provided in different embodiments. In otherembodiments, the jar 102 may be of any other suitable shape and mayinclude an internal surface that may be smooth, rough, and/or compriseany suitable texture.

Containers of various sizes for containing pharmaceutical compositionexist in the market, such as (i) containers in which compounds aretraditionally dispersed by an electric mortar/pestle and (ii) containersfrom which compounds are dispensed (such as bottles and syringes). Aswill be discussed later in this text, the system 10 may be configured toimplement the superimposed revolution and rotation movements describedhere in containers/jars of various sizes.

FIG. 8 shows an example container 402 in which pharmaceuticalcomposition ingredients would traditionally be dispersed by an electricmortar/pestle. One example of the container 402 is referred to in theindustry as an Unguator™ jar (available from GAKO Konietzko GmbH,Bamberg, Germany), although recently similar containers have been madeavailable by Samix GmbH, Zella-Mehlis, Germany.

The container 402 includes a body 404 and a cover 406. The body 404 andthe cover 406 may be complementarily threaded. The cover 406 includes anozzle 408, which may include an external thread 408A to receive aninternally threaded cap 410. The cap 410 has an external diameterdenoted 410A. The nozzle 408 has an aperture 412 that allows fluid toescape die container 402 when the cap 410 is removed and a piston (notshown) is pushed from underneath the body 404. For electricmortar/pestle mixing, the cap 410 is removed from the cover, the cover406 is removed from the body 404, a blade shaft (not shown) is insertedfrom underneath the cover 406 and through the aperture 412 and connectedto a motor (not shown); meanwhile, the body is filled with thecomposition ingredients to be dispersed, then the blade is positionedinside the body 404 and the covet 406 is secured back onto the body 404.

FIG. 9 shows alternative containers 502A, 502B and 502C. The containers502A, 502B and 502C include a respective cylindrical body 504, 504′ and504″, and an actuator 506. The actuator 506 can be actuated by a user todispense a composition contained in the body 504. Depending on theembodiment, the actuator 506 may in fact allow metered dispensing of thecomposition.

As is apparent from the above, the containers used for dispersingpharmaceutical composition ingredients (e.g., containers 402, 502A) donot necessarily correspond to the jar 102. As such, in accordance withvarious embodiments, and with reference to FIG. 10B, there is providedan adapter 602 between the jar 102 and the container 600 (generallyreferred to by 600 but which could be one of the aforementionedcontainers 402, 502A). The container 600 has a smaller volume than thejar 102 and is secured to an interior of the jar 102 by the adapter 602.The adapter is designed not to hold the composition but rather to securethe container 600 to the jar 102. The ability to secure a container 600with a smaller volume entirely within the jar 102 can allow smallerquantities of pharmaceutical composition ingredients to undergoefficient dispersing despite the small amount of the composition.

In one embodiment, the jar 102 may have a volume of approximately 250ml, while the container 600 may have a volume of approximately 100 ml,or approximately 80 ml, or approximately 50 ml, or approximately 35 ml,or approximately 30 ml, or approximately 20 ml or approximately 15 ml.It should be appreciated that a height-to-base ratio (HBR) associatedwith a certain quantity of a composition to be dispersed in a particularvessel may be defined as the quotient between a height dimensionoccupied by the quantity of the composition and a base dimensionoccupied by the quantity of the composition, when that quantity isplaced into the particular vessel. The HBR may be a parameter indicativeof how efficiently the composition will be dispersed, where moreefficient dispersing could be defined as reaching the same degree ofhomogeneity earlier in die dispersion process, or reaching a higherdegree of homogeneity at the same duration of dispersion.

With continued reference to FIG. 10A, there is shown an example quantityof composition 610 placed in the jar 102 and with reference to FIG. 10B,the same quantity of composition 612 placed in the container 600 that issecured to the jar 102 by the adapter 602. The height dimension occupiedby the composition 610 in the jar 102 is given by HJ and the basedimension is given by the bottom inside diameter 206 of the jar 102,which can be referred to as B206. Thus, the HBR associated with thequantity of composition 610 is HJ/B206 for the jar 102. Turning now tothe case of the container 600, it is seen that the height dimensionoccupied by the composition 612 in the container 600 is given by HC andthe base dimension is given by the bottom inside diameter of thecontainer 600, which can be referred to as BC. Thus, the HBR associatedwith the quantity of composition 612 is HC/BC for the container 600.

It should be apparent, therefore, that for the same quantity ofpharmaceutical composition, the HBR for the container 600 is greaterthan for the jar 102. In fact, the smaller the quantity of thecomposition, the greater the difference in HBR between the jar 102 andthe container 600. This increase in HBR from the jar 102 to thecontainer 600 (for the same quantity of composition) is a function ofthe ratio between the base area of the jar and the base area of thecontainer. For certain quantities of ingredients and certain containersizes, the HBR will fall outside a desired range (e.g., 0.75 to 1.5, or0.75 to 1.33, or even 1 to 1.25) if the composition is placed directlyin the jar 102 and will be closer to, or within, the desired range, ifthe composition is placed in the container 600.

Another parameter that could be indicative of how efficiently thecomposition will be dispersed may be “percent volume occupancy” (PVO).For a quantity of composition in a vessel with a generally cylindricalinternal volume, the PVO may be defined as the ratio of the heightdimension occupied by the composition to the overall interior heightdimension of the vessel. In due example of FIG. 10A, the PVO for the jar102 is clearly under 20%, whereas for the container 600 in FIG. 10B itis over 50%. It should be apparent, therefore, that for the samequantity of composition, the PVO for the container 600 is greater thanfor the jar 102. In fact, the smaller the quantity of the composition,the greater the difference in PVO between die jar 102 and the container600.

Expressed another way, the use of the container 600 with the jar 102 canallow a composition that occupies ½ of the jar capacity to have an HBRbetween 0.75 and 1.5 (or between 0.75 and 1.33, or even between 1 and1.25) when the composition is placed into the container 600.

As such, it may be more desirable to utilize a container 600 having acertain size, rather than the jar 102, in order to process smallerquantities of composition, so as to obtain a more suitable HBR or PVO.This is especially the case when the quantity of the composition to beprocessed is less than half the capacity of the jar 102 or less than aquarter of the capacity of the jar or less than a tenth of the capacityof the jar.

To allow the use of a smaller container with improved HBR or PVO, theadapter 602 may help reduce or prevent tattling and other instabilitieswithin the jar 102 during processing by the apparatus 100. The adapter602 is disposed between the interior of the jar 102 and the exterior ofthe container 600. When the adapter 602 is attached to the container600, it can be inserted into and removed from the jar 102, and for thisreason the container 600 together with the adapter 602 may be referredto as a removable “containing system” 606.

Different embodiments of the adapter 602 may be provided for differentversions of the container 600. Thus, depending on whether the container600 is a compounding bottle with a nozzle (such as container 402) or acylindrical bottle (such as container 502A), the adapter 602 may take ona different shape or structure. This is now described in some detail.

FIG. 11 shows a non-limiting embodiment of an adapter 700 for use with anozzled container, such as the container 402. The adapter 700 may be inthe form of a disk with an aperture 702 in the center thereof. Theadapter 700 occupies an area in 3-dimensional space that is outlined byan envelope 704. The adapter 700 may be populated with voids 706 thatreduce the weight of the adapter and therefore the density of theadapter 700 vis-à-vis the envelope 704 that it occupies. In someembodiments, the voids 706 are evenly spaced circumferentially and givethe adapter 700 the appearance of a wheel.

In some embodiments, the adapter 700 is configured to attach to acontainer with a nozzle, such as the container 402 previously described.To this end, the aperture 702 has a dimensionality that is selectedaccording to the configuration of the nozzle 408 of the container 402.In particular, FIG. 12 shows details of the external threads 408A on thenozzle 408 and the adapter 700 shown in FIG. 11 may accordingly includeinternal threads 708 in the area of the central aperture 702 so as toenable the adapter 700 to be screwed onto the nozzle 408. It should beappreciated that when nozzled containers of different sizes all sharethe same design of the nozzle 408, the same adapter 700 may be used forthese various containers.

FIG. 13 shows an alternative non-limiting embodiment of an adapter 900,also including an aperture 902, but where the aperture 902 is madeslightly wider than the aperture 702 and in fact slightly wider than themaximum diameter of the external threads 408A of the nozzle 408.However, the width of the aperture 902 is smaller than the externaldiameter 410A of the cap 410 (shown in FIG. 8). Thus, when the adapter900 is placed over the nozzle 408 and then the cap 410 is threaded ontothe nozzle 408, the adapter 900 ends up being enclosed between the cover406 and the cap 410.

The adapters 700, 900 may have a thickness of between 0.5 mm and 5 mm,or even between 1 and 3 mm, although it may be thinner in someembodiments and thicker in others. Other design considerations include(i) that there be sufficient threading 408A in the nozzle 408 to allowthe cap 410 to be securely mounted thereto and (ii) once the cap 410 ismounted to the nozzle 408 (on top of the adapters 700, 900) and acontaining system 606 is positioned in the jar 102, that there besufficient clearance (the minimum being zero, i.e., flush) between thetop of the cap 410 and the underside of the lid 106 of the jar 102 oncethe lid 106 has been mounted to the mouth 108 of the jar 102.

To mitigate lateral rattling, the containing system 606 should fitfrictionally within the jar 102. To this end, with reference to FIG. 14,the adapter 602 is seen as having a cross-sectional width 1002 that issubstantially equal to the cross-sectional width 108W of the mouth 108of the jar 102. When the containing system 606 is placed into the jar102, the maximum space between the outer edge of the adapter 602 and theinner surface 218 of the jar 102 may be less than 2 mm, in some casesless than 1 mm and in some cases less than 100 microns.

It should be appreciated that although it is important that there besufficient clearance between the top of the cap 410 (mounted to theadaptors 700, 900) and the underside of the lid 106 of the jar 102 oncethe lid 106 has been mounted to the mouth 108 of the jar 102, excessiveclearance could allow motion along the main axis 608 of the containingsystem 606 during mixing by the mixing apparatus 100. (Of course, themain axis 608 is shown as being vertical in the drawings, but in use, itis recognized that the jar 102 sits at an angle, and therefore the mainaxis 608 will be oblique). Excessive clearance is caused by the smallercontainer sizes that do not have sufficient height dimensions, such thatwhen the adapters 700, 900 are used, the ensuing containing system 606would still be free to travel in a piston like fashion.

With reference to FIG. 15, there is shown an alternative embodiment ofan adapter 1100, which may be useful with smaller container sizes. Theadapter 1100 includes a disk 1102 and a band 1104 that surrounds andextends upwardly from the disk 1102. The disk 1102 has a centralaperture 1106 that could be similar to the aperture 702 in FIG. 11(which is internally threaded to engage the external thread 408A of thenozzle 408) or to the aperture 902 in FIG. 13 (which is wider than thenozzle 408). The band 1104 includes a ring 1108 and, optionally, a lip1110. The ring 1108 has an outside diameter 1112 than is substantiallyequal to the top inside diameter 202 of the jar 102. The lip 1110extends radially outwardly beyond the ring 1108, but only slightly, asit is configured to rest on the mouth 108 of the jar 102 withoutprotruding radially from the jar 102. The lip 1110 therefore also has acircular shape and its maximum diameter corresponds to the outerdiameter 220 of the jar body 102. The ring 1110 therefore fitsfrictionally into the jar 102, descending towards the middle section 214of the jar 102, while the lip 1110 acts as a stopper to prevent the ring1108 from being pushed too deep into the jar 102. The lid 106 may stillbe placed onto the mouth 108 of the jar 102, although in reality it isbeing placed onto an upper surface of the lip 1110. Thus, the height ofthe jar is increased by no more than 1 or 2 mm, on top of which the lid106 is positioned.

As shown in FIG. 16, the adapter 1100 may be attached to the container402 between the top surface of the cover 406 and the bottom surface ofthe cap 410. When the containing system 606 is placed in the jar 102, arange of smaller sizes of containers 402 can be seemed in place by theadapter 1100. In particular, assuming that they all share the samenozzle 408 and cap 410 configuration, the largest size container 402will be the one whose bottom 1114 touches the bottom of the inside ofthe bottom surface of the jar 102 when attached to the adapter 1100 ofFIGS. 15 and 16.

Thus, smaller sizes of the container 402 can be accommodated by theadapter 1100. In particular, containers having less height can beaccommodated by attaching the adapter 1100 in exactly the same way. Thedifference is that the container will now be suspended within the jar.This is shown in the cross-sectional drawing of FIG. 17. In particular,it is seen that no direct contact exists between the container 1302 andthe inner wall 218 of the jar 102. Rather, the adapter 1100 provides theonly contact with inner wall 218 of the jar 102. However, this is not arequirement. For example, in other embodiments (not shown), the cap 410that is threaded onto the nozzle 408 of the container 1302 may contactthe underside of the lid 106 of the jar 102. An advantage of the adapter1100 of FIGS. 15 to 17 may be that the same adapter 1100 can accommodatedifferent size nozzled containers, for example, 50 ml, 30 ml or 20 ml,to name a few non-limiting possibilities.

It should be appreciated that for certain container sizes, although thecontainer 1302 is suspended within the jar 102 at rest by the adapter1100, during operation, there may be contact between the outer wall ofthe container 1302 and the inner wall 218 of the jar 102. This may becaused by the high centrifugal force exerted by the apparatus 100 on thecontaining system 1306 (i.e., the adapter 1100 and the container 1302,including its contents), which could temporarily deform the container1302 and/or the adapter 1100 to a point where at least a portion surfaceof the container 1302 makes direct contact with the inner wall 218 ofthe jar 102.

In another embodiment, the container that contains the composition to bedispersed does not have a cover with a threaded nozzle. Rather, thecontainer may be a cylindrical container with a substantially smooth andeven cylindrical profile. In this case, the adapter may be configured toclamp the container from the sides.

Specifically, FIGS. 18A and 18B each show an embodiment of an adapter1400 at rest, including a base 1402 and a plurality of prongs 1404distributed circumferentially. The adapter 1400 defines a centralopening 1414 into which a container such as the container 502A may beinserted and surrounded by the prongs 1404. The adapter 1400 has aheight dimension 1406 that may correspond substantially to the insideheight of the jar 102. The prongs 1404 may be resilient and slightlyoutwardly biased. As such, when the adapter 1400 is at rest (outside thejar 102, as shown in FIGS. 18A and 18B), the prongs 1404 define asubstantially band-like cross-section 1408 with an inside width 1410 andan outside width 1412. The inside width 1410, near the top of theadapter 1400, is slightly greater than an outside diameter 508 of thecontainer 502A for which it is configured. Thus there is a gap 1502 asshown in FIG. 19. Also, at test, the outside width 1412, near the top ofthe adapter 1400, is slightly greater than the top inside diameter 202of the jar 102 (see FIG. 1). As will now be explained, there is enoughresiliency in the prongs 1404 so that they may be compressed radiallyinwardly.

In particular, FIG. 20 shows a cross-sectional view of the adapter 1400when the containing system 1600 (including the adapter 1400 and thecontainer 502A) is placed inside the jar 102. Here, the prongs 1504 arecompressed inwardly (towards the center) and the inside width 1410 ofthe band-like cross-section 1408 formed by the prongs 1404 is nowsubstantially the same as the outside diameter 508 of the container 502Aand the outside width 1412 of the band-like cross-section formed by theprongs 1404 is now substantially the same as the top inside diameter 202of the jar 102. As a result, the container 502A is more snuglymaintained by the prongs 1404 within the central opening 1414.

The number of prongs 1404 is not particularly limited. The embodiment ofFIGS. 18A and 18B show the adapter 1400 having three prongs 1404.However, in other embodiments, such as in FIG. 21, the adapter 1700 hasfour prongs 1704.

To limit the amount of material used to make the adapter 1400, 1700, theadapter may include cut-outs 1418, 1718 between the prongs 1404, 1704.The cut-outs have a depth defined as a relative distance occupied by thecut-outs in a height dimension of the adapter compared to the overallheight of the respective adapter 1400, 1700. For example, for theadapter 1700 for which a side elevational view is shown in FIG. 21, thedepth of the cut-outs 1718 is over 50%. In other embodiments, such asfor the adapter 1400 for which a side elevational view is shown in FIG.18, the depth of the cut-outs 1418 may be over 60%, over 70% or evenover 80%. In further embodiments, it may be between 40% and 50%.

The cut-outs 1418, 1718 may take on different shapes and configurations.In FIGS. 18B and 21, the cut-outs 1418, 1718 have a deep parabolicshape. In other embodiments, the cut-outs may have a mote square-like(or rectangular) appearance.

In certain embodiments, as shown in FIG. 19, the container 502A mayinclude a vertical viewing window 1504 that allows a user to see a levelto which the container 502A is filled. Accordingly, the cut-outs 1418may be shaped so as to allow at least part of the viewing window 1504 tobe unobstructed.

Turning back to FIG. 18, with additional reference to FIG. 14, the base1402 of the adapter 1400 may be circular and may have a diameter D1402that is substantially identical to the top inside diameter 202 of thejar 102, or even slightly greater than it (e.g., corresponding to themiddle inside diameter 204 or by up to 1 mm or even 2 mm larger). Thus,aligning the base 1402 of the adapter 1400 with the mouth 108 of the jar102 may make it difficult or even impossible to fit the adapter 1400into the jar 102. Thus, a different technique for insetting the adapter1400 into the jar 102 may be required. To this end, the base 1402 can betilted and then placed onto the mouth 108 of the jar 102, such that onlytwo diametrically opposite extremities 1419, 1420 of the base 1402 arein contact with the inner surface 218 of the jar at respective contactpoints 222, 224 of the adapter 1400. The adapter 1400 is then urged intothe jar, which causes a very slight expansion of the width of the mouth108, while resulting in a contraction of the mouth elsewhere between thetwo aforementioned contact points 222, 224. However, since the adapter1400 is not in contact with these contracting regions, the jar 102 isallowed to flex, and thus allows the adapter 1400 to slip into the jar102. Once the two contact points 222, 224 of the adapter 1400 pass thetop section 212 of the jar 102 (which has the smallest width, namely thetop inside diameter 202) and move to the middle section 214 of the jar102 (which has the second-smallest width, namely the middle insidediameter 204), the mouth 108 of the jar 102 returns back to its originalshape, which may be circular.

It should be appreciated that in the case of the container 502A, with acylindrical exterior shape, the actuator 506 may be provided so that themixed composition can be dispensed to an end user without the need fortransfer into a separate dispenser. Of course, the actuator 506 takes uppart of the headroom available between the container 502A and theunderside of the lid 106, thus limiting the volume of the compositionthat can be placed m the body 504 for mixing. Thus, it is possible toprovide a container consisting primarily of the body 504 but without theactuator 506. In this case, a temporary cap (not shown) could be fittedon the container body 504, with the temporary cap being relatively short(a height less than that of the actuator 506) and having a maximum widththat is no wider than the body 504 of the container 502A. After mixing,the temporary cap may be removed, and replaced with the actuator 506.Because the temporary cap can be designed with a smaller heightdimension than the actuator 506, higher (i.e., more voluminous)containers may be accommodated.

Those ordinarily skilled in the art will appreciate that furtherimprovements may be made to the design of die adapter. In particular, inthe case where an adapter is designed that has a maximum width that isless than the width of the jar, rotational motion of the jar may induceslippage in the containing system (which includes the adapter and thecontainer). The amount of slippage may further be a function of thedimensions of the container and the weight and/or volume of thecomposition contained therein. To reduce slippage, various possibleanti-slippage mechanisms may be provided, depending on operationalrequirements.

Firstly, FIG. 22 shows an adapter 2100 fitted with a rubberized exteriorperipheral band 2012. In another example, as shown in FIG. 23, the innersurface 218 of the jar 102 may be provided with an engaging element 2202and an adapter 2200 may be provided with a complementary engagingelement 2204 that engages with the engaging element 2202. For example,one of the engaging elements 2202, 2204 may be a slot, while the otherone of the engaging elements 2202, 2204 may be a protrusion or pin. Ofcourse, many other forms of complementary engaging elements may bedevised that inhibit rotational motion of the adapter 2200 and/or thecontaining system within the jar 102.

Those skilled in the art will recognize that further improvements may bemade to enhance performance during the herein described bladelessdispensing pattern process. For example, in the event that the userwishes to mix a composition that gives off heat, such heat may damagethe API of the composition above a certain temperature, known as thedegradation temperature threshold. With additional reference to FIG. 24,it is within the scope of the present invention to delay teaching thistemperature by providing a heat conductive material 2304 between theadapter 1400 (or 1700) and the inner surface 218 of the jar 102. Theheat conductive material 2304 may serve to dissipate heat better thansimply the air that would ordinarily occupy this space. In some cases, athermally conductive foil, foam or gel may be provided, as are madeavailable by Fischer Elektronik GmbH, Lüdenscheid, Germany.

In another embodiment, rather than a thermally conductive material, itmay be desirable to place a thermally insulating material 2404 betweenthe adapter 1400 and the inner surface 218 of the jar 102, as shown inFIG. 25. The insulating material 2404 may serve as a barrier to heatleaving the container 502A, which will result in an increase in thetemperature within the container 502A. As a result, it may be possibleto melt the compound that is undergoing the herein described bladelessdispensing pattern process within the container 502A, thereby leading toa state change of the composition through novel use of the apparatus100. Moreover, the use of the heat insulating material 2404 mayaccelerate the melting process, i.e., shortening the time it takes tomelt the composition, thus leading to a more efficient usage of theapparatus 100.

With reference to FIG. 26, there is shown an insert 2502 that may beremovably positioned within the jar 102. The insert 2502 has the form ofa metallic cup with a bottom, but in other embodiments it may be abottomless sleeve. The insert 2502 may be made of hardened steel,stainless steel, tungsten carbide, agate, sintered aluminium oxide,silicon nitride or zirconium oxide, for example. Also provided aregrinding media 2504 such as balls or pellets made of similar materials,as shown in FIG. 27. In an embodiment, the insert 2502 is frictionfitted to the inner surface 218 of the jar 102 and may have a thicknessof between 10 and 100 mils, although other thicknesses are possible. Inanother embodiment, the insert 2502 may have a smaller volume and may beheld in place within the jar by an adapter, which may be similar to thepreviously described adapters. As a result, it may be possible to grindingredients of the compounding composition through novel use of theapparatus 100.

Definitions

Compounding activities, in the context of the present specification,also applies to combining, mixing or altering ingredients for a cosmeticcomposition which may include active over the counter (OTC) ingredientsor prescription pharmaceutical ingredients. Within the context of thepresent specification, OTC and prescription ingredients are encompassedby the expression “active pharmaceuticals ingredients” (i.e., “API”).

Examples of active pharmaceuticals ingredients (APIs) include, but arenot limited to, antibiotics, analgesics, vaccines, anticonvulsants;antidiabetic agents, antifungal agents, antineoplastic agents,antiparkinsonian agents, anti-rheumatic agents, appetite suppressants,biological response modifiers, cardiovascular agents, central nervoussystem stimulants, contraceptive agents, dietary-supplements, vitamins,minerals, lipids, saccharides, metals, amino acids (and precursors),nucleic acids and precursors, contrast agents, diagnostic agents,dopamine receptor agonists, erectile dysfunction agents, fertilityagents, gastrointestinal agents, hormones, immunomodulators,antihypercalcemia agents, mast cell stabilizers, muscle relaxants,nutritional agents, ophthalmic agents, osteoporosis agents,psychotherapeutic agents, parasympathomimetic agents, parasympatholyticagents, respiratory agents, sedative hypnotic agents, skin and mucousmembrane agents, smoking cessation agents, steroids, sympatholyticagents, urinary tract agents, uterine relaxants, vaginal agents,vasodilator, anti-hypertensive, hyperthyroid, anti-hyperthyroid,anti-asthmatics and vertigo agents.

In certain embodiments, the API is a poorly water-soluble drug or a drugwith a high melting point.

The API may be found in the form of one or more pharmaceuticallyacceptable salts, esters, derivatives, analogs, prodrugs, and solvatesthereof. As used herein, a “pharmaceutically acceptable salt” isunderstood to mean a compound formed by the interaction of an acid and abase, the hydrogen atoms of the add being replaced by the positive ionof the base. Non-limiting examples of pharmaceutically acceptable saltsinclude sulfate, citrate, acetate, oxalate, chloride, bromide, iodide,nitrate, bisulfate, phosphate, add phosphate, isonicotinate, lactate,salicylate, add citrate, tartrate, oleate, tannate, pantothenate,bitartrate, ascorbate, succinate, maleate, gentisinate, fumarate,gluconate, glucaronate, saccharate, formate, benzoate, glutamate,methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate,and pamoate. Another method for defining the ionic salts may be as anacidic functional group, such as a carboxylic add functional group, anda pharmaceutically acceptable inorganic or organic base. Non-limitingexamples of bases include, but are not limited to, hydroxides of alkalimetals such as sodium, potassium and lithium; hydroxides of calcium andmagnesium; hydroxides of other metals, such as aluminum and zinc;ammonia; and organic amines, such as unsubstituted or hydroxysubstituted mono-, di-, or trialkylamines; dicyclohexylamine;tributylamine; pyridine; N-methyl-N-ethylamine; diethylamine;triethylamine; mono-, bis- or tris-(2-hydroxy-lower alkyl amines), suchas mono-bis- or tris-(2-hydroxyethyl)amine, 2-hydroxy-tert-butylamine,or tris-(hydroxymethyl)methylamine, N,N-di-lower alkyl-N-(hydroxy loweralkylamines, such as N,N-dimethyl-N-(2-hydroxyethyl)amine, ortri-(2-hydroxyethyl)amine; N-methyl-D-glucamine; and amino acids such asarginine, lysine, and the like.

The APIs may be used in a variety of application modalities, includingoral delivery as tablets, capsules or suspensions; pulmonary and nasaldelivery; topical delivery as emulsions, ointments or creams;transdermal delivery; and parenteral delivery as suspensions,microemulsions or depot.

For the purpose of the present disclosure, the pharmaceuticallyacceptable excipient, diluent or carrier may be a solid, semi-solid(more or less viscous fluid) or fluid (for example a cream or anemulsion). The person of skill will appreciate that pharmaceuticallyacceptable excipients, diluents or carriers are known in the art and mayinclude, but without being limited thereto, anti-adherents such asmagnesium stearate; binders, such as saccharides and their derivatives(sucrose, lactose, starches, cellulose or modified cellulose, sugaralcohols such as xylitol, sorbitol or maltitol), proteins such asgelatins, synthetic polymers such as polyvinylpyrrolidone (PVP) orpolyethylene glycol (PEG); coloring dyes or fragrance; glidants such asfumed silica, talc, and magnesium carbonate; hydrophilic or hydrophobiclubricants such as talc or silica, and fats, e.g. vegetable stearin,magnesium stearate or stearic acid; preservatives such as antioxidantvitamins or synthetic preservatives like parabens; sorbents or otherdesiccant; vehicles that serve as a medium for conveying the activeingredient such as petrolatum, gum base gelatin, dimethyl sulfoxide andmineral oil or commercial products such as VersaPro™ Gel, HRT™ Cream,OleaBase™ Plasticized, PLO Gel Mediflo™, Oral Mix™ or VersaPro™ cream,all from Medisca Pharmaceutique (Canada).

For the purpose of the present disclosure, the compounding compositionsof the present description may be adapted for oral, rectal, vaginal,topical, urethral, ocular, or transdermal administration.

EXAMPLES

Details of specific practical implementation of die present disclosurewill be further described in the following examples.

Example 1

In the following experiment, a compounding composition of 150 mlincluding 10% progesterone dispersed in an excipient was preparedaccording to the herein described superimposed revolution and rotationmovements. The characteristics of the resulting composition wereassessed.

In a dispersing container, 15 g of USP micronized progesterone (NDC:0043-08, Lot: 56345/B) was levigated with 12.5 mL of ethoxy diglycol byhand. The container was then filled with 122.75 mL of pharmaceuticallyacceptable excipient VersaPro™ Cream (NDC: 2529-01, Lot: 56035D), andplaced in a planetary mixer (Mazerustar KK-250S). The parameters foroperating the superimposed revolution and rotation movements were set,including revolution, rotation and rime variables. The resultingdispersed 10% progesterone composition was separated in the containerinto three layers, namely top (I), middle (M) and bottom (B) layers.

The progesterone concentration of each layer was determined using highperformance liquid chromatography (HPLC). The person of skill will beable to determine the HPLC assay parameters without undue effort as HPLCis a known technique. The standard deviation (SD) between theprogesterone concentrations of the three layers for each preparedformulation was determined. The design of experiment (DOE) was setup asa 23 full factorial design. Explanatory operating parameters included:revolution (×1), rotation (×2) and time (×3). The response variable (y1)was defined as the standard deviation (SD) between the concentrations ofprogesterone from three separated layers of the prepared composition inthe dispersing container. Coding of these variables with respect tomixer settings are shown in Table 1.

TABLE 1 Coding of Explanatory Variables KK-250S Mixer SettingExplanatory Low Value Centre Point Value High Value Coding Variables(-1) (0) (+1) Equation Revolution, x1 1 5 9 $\frac{{x1} - 5}{4}$Rotation, x2 1 5 9 $\frac{{x2} - 5}{4}$ Time, x3 1 (10 s) 7 (70 s) 15(150 s) $\frac{{x3} - 8}{7}$

Eight experimental runs were executed at boundary conditions and threewere done at centre point values as set forth in Table 2

TABLE 2 Trial parameters Randomized Trial Formulation Runs Mixer EthoxyTrial Setting Progesterone Diglycol VersaPro Mass of Samples [g] x1 x2x3 Run # x1 x2 x3 [g] [g] [g] Top Middle Bottom 1 1 1 1 9 9 15 15.03512.912 122.574 48.918 48.311 41.019 0 0 0 2 5 5 7 15.069 12.956 122.49244.109 45.606 49.642 −1 −1 −1 3 1 1 1 15.037 12.895 122.009 49.09745.395 52.768 −1 1 1 4 1 9 15 15.053 13.052 122.652 44.340 46.901 55.213−1 −1 1 5 1 1 15 15.048 12.849 122.816 50.134 46.522 51.165 1 1 −1 6 9 91 15.083 12.826 122.695 50.382 50.591 45.714 0 0 0 7 5 5 7 15.030 12.744122.454 49.940 45.959 5.454 1 −1 −1 8 9 1 1 15.012 12.778 122.784 48.31144.961 54.641 1 −1 1 9 9 1 15 15.024 12.811 122.705 48.878 49.262 48.490−1 1 −1 10 1 9 1 15.054 12.725 122.615 49.342 49.447 49.141

Trials were randomized and the results are found in Table 3:

TABLE 3 Percent Progesterone and Standard Deviation Values for EachFormulation Percent Average Relative Proges- Top, Middle, Concen-Standard Standard Sample terone Bottom tration Deviation Deviation #(w/w) layers (w/w) (SD) (RSD) (%) 1 9.0 T 9.3 0.351 3.77 2 9.3 M 3 9.7 B4 9.7 T 9.7 0.300 3.09 5 9.4 M 6 10.0 B 7 1.2 T 5.9 4.392 74 8 6.6 M 99.9 B 10 8.2 T 9.5 2.166 22 11 8.3 M 12 12.0 B 13 3.3 T 9.4 10.078 10714 3.8 M 15 21.0 B 16 9.7 T 9.5 0.346 3.64 17 9.1 M 18 9.7 B 19 9.8 T9.6 0.208 2.17 20 9.7 M 21 9.4 B 22 1.1 T 7.8 8.997 115 23 4.2 M 24 18.0B 25 7.1 T 8.8 3.659 41 26 6.3 M 27 13.0 B 28 4.2 T 9.1 8.545 93 29 4.2M 30 19.0 B

The mixing process can be modeled by the following predictive cubicregression:

$\begin{matrix}{{{SD}\mspace{14mu} {Percent}\mspace{14mu} {Progesterone}} = {3.886 - {1.478\left( \frac{x_{1} - 5}{4} \right)} - {1.965\left( \frac{x_{2} - 5}{4} \right)} - {0.620\left( \frac{x_{3} - 8}{7} \right)} - {1.025\left( \frac{x_{1} - 5}{4} \right)\left( \frac{x_{2} - 5}{4} \right)} - {0.580\left( \frac{x_{1} - 5}{4} \right)\left( \frac{x_{2} - 8}{7} \right)} - {0.840\left( \frac{x_{2} - 5}{4} \right)\left( \frac{x_{3} - 8}{7} \right)} + {2.176\left( \frac{x_{1} - 5}{4} \right)\left( \frac{x_{2} - 5}{4} \right)\left( \frac{x_{3} - 8}{7} \right)}}} & {{equa}.\mspace{14mu} (1)}\end{matrix}$

In the equation (1), x₁ is the revolution setting, x₂ is the rotationsetting and x₃ is the time setting.

The combined effect of revolution, rotation and time was found to havethe greatest effect, followed by rotation and revolution. The timesetting x₃ by itself, was not statistically significant. The interactioneffects were found to be relatively influential, particularly thecombination effect of all three parameters. The interaction effects canbe seen in FIG. 28.

The model was reduced through an iterative method in order to betterobserve the parameter and interaction effects on a more statisticallysignificant level. The codependency of the revolution, rotation and timewas observed to have the strongest effect on the SD of progesteroneconcentration, followed by rotation and revolution. As expected, fasterrotation and revolution speeds, decreased the SD of percentprogesterone. These relationships are illustrated in FIG. 29.

The reduced model can be represented by the following reduced equation:

$\begin{matrix}{{{SD}\mspace{14mu} {Percent}\mspace{14mu} {Progesterone}} = {3.904 - {1.478\left( \frac{x_{1} - 5}{4} \right)} - {1.965\left( \frac{x_{2} - 5}{4} \right)} + {2.176\left( \frac{x_{1} - 5}{4} \right)\left( \frac{x_{2} - 5}{4} \right)\left( \frac{x_{3} - 8}{7} \right)}}} & {{equa}.\mspace{14mu} (2)}\end{matrix}$

In equation 2, x₁ is the revolution setting, x₂ is the rotation settingand x₃ is the time setting.

Based on the cubic regression model (equation 1), a desirabilityalgorithm was derived for optimization of the dispersing process. Foroptimal conditions, desirability was set such that SD of percentprogesterone was zero and the time setting was minimized to the lowestvalue (i.e., 10 seconds). It was found that ideal conditions could bemet given the following mixer settings: revolution=9, rotation=9 andtime=1. This optimization is shown in FIG. 30.

Example 2

In this example, the superimposed revolution and rotation movements wereperformed in a planetary mixer (Mazerustar kk-300ss) in presence ofgrinding media. The following assays surprisingly demonstrated that theherein described superimposed revolution and rotation movements can beused to grind particles in presence of grinding media to obtain adesirable particle size distribution, while maintaining the temperatureof the materials being grinded at a safe level below typical degradationtemperature of thermally labile API.

Briefly, the container was filled with grinding media and sodiumchloride for a total volume of 32 ml, and the superimposed revolutionand rotation movements were performed at 1000 rpm (revolution) and 400rpm (rotation) for 60 seconds with either sphere grinding media of 8 mm(58 beads) or cylinder grinding media of 10 mm (37 beads). A controlgrinding experiment was performed using mortar and pestle of sodiumchloride.

A first assay was performed with 20 g of sodium chloride (NDC 0629-08;lot number 602576/B, melting temperature of 801° C.). FIG. 31A showsthat the sodium chloride prior to processing had the following particlesize distribution (PSD) in μm: D₁₀ of 225.563, D₅₀ of 354.819 and D₉₀ of539.090. FIG. 31B shows that the control experiment of mortar and pestlefor 60 seconds demonstrated virtually no change in the PSD, with thefollowing values in μm: D₁₀ of 171.989, D₅₀ of 328.938 and D₉₀ of548.544. FIG. 31C shows that in contrast, grinding with spheres of 8 mmsignificantly shifted the PSD to the following lower values in μm: D₁₀of 8.476, D₅₀ of 43.919 and D₉₀ of 126.183, while maintaining thetemperature of the mixture at a safe level below typical degradationtemperature of thermally labile API. Similarly, FIG. 31D shows thatgrinding with cylinders also significantly shifted the PSD to thefollowing lower values in μm: D₁₀ of 11.835, D₅₀ of 64.803 and D₉₀ of181.616, while maintaining the temperature of the mixture at a safelevel below typical degradation temperature of thermally labile API. Theresults are also reported in the following Table 4:

TABLE 4 Grinding of sodium chloride Mortar Grinding Grinding and MediaMedia Control Pestle (spheres) (cylinders) Surface 297.087 194.68018.511 25.690 Weighted Mean (μm) Volume 367.953 343.262 57.384 99.796Weighted Mean (μm) D₁₀ (μm) 225.563 171.989 8.476 11.835 D₅₀ (μm)354.819 328.938 43.919 64.803 D₉₀ (μm) 539.090 548.544 126.183 181.616Temp.  24.7/NA 24.5/24.1 24.7/39.8 25.9/36.9 before/ after (° C.) Weight5.016/NA 20.012/19.989 20.027/19.887 20.025/19.908 before/ after (g)

Similar results were obtained when milling 30 g of sodium chloride usinga mix of bead sizes, namely 80 beads were 8 mm and 25 beads were 6 mm,for a total weight of 310 g. Qualitative assessment of grinding efficacywas also performed in the planetary mixer using as starting material,granular sodium chloride at 10 g, 20 g or 30 g with 45 beads (spherical)of 8 mm filling the bottom layer of the container, for 60 sec at 1000rpm. The results are that the various weights of materials wereeffectively grinded with these parameters.

A second assay was performed with Gabapentin (NDC 2461-05; lot number607832/B; melting temperature of 162° C.). FIG. 32A shows that the APIprior to milling had the following particle size distribution (PSD) inμm: D₁₀ of 9.688, D₅₀ of 59.399 and D₉₀ of 164.334. FIG. 32B shows thatthe control experiment of mortar and pestle for 60 seconds demonstratedvirtually no change in the PSD, with the following values in μm: D₁₀ of8.033, D₅₀ of 53.500 and D₉₀ of 163.239. FIG. 32C shows that incontrast, grinding with spheres for 60 seconds at 1000 rpm (revolution)and 400 rpm (rotation) significantly shifted the PSD to the followinglower values in μm: D₁₀ of 1.524, D₅₀ of 9.170 and D₉₀ of 58.913, whilemaintaining the temperature of the mixture at a safe level below thedegradation temperature of the API. Similarly, FIG. 32D shows thatgrinding with cylinders for 60 seconds at 1000 rpm also significantlyshifted the PSD to the following lower values in μm: D₁₀ of 3.878, D₅₀of 33.616 and D₉₀ of 150.820, while maintaining the temperature of themixture at a safe level below the degradation temperature of the API.

The results are also reported in the following Table 4A:

TABLE 4A Grinding of Gabapentin Mortar Grinding Grinding and Media MediaControl Pestle (spheres) (cylinders) Surface 21.005 18.094 3.826 10.126Weighted Mean (μm) Volume 76.316 81.389 25.998 91.378 Weighted Mean (μm)D₁₀ (μm) 9.688 8.033 1.524 3.878 D₅₀ (μm) 59.399 53.500 9.170 33.616 D₉₀(μm) 164.334 163.239 58.913 150.820 Temperature  24.2/NA  23.8/25.1 24.1/37.4  24.6/29.8 Before/ After (° C.) Weight 2.508/NA 10.003/9.79710.011/9.292 10.019/9.599 Before/ After (g)

Similar results were obtained when milling 15 g of Gabapentin using amix of bead sizes, namely 80 beads were 8 mm and 42 beads were 6 mm, fora total weight of 310 g.

Other experiments were also made with the following starting materialand grinding media using higher settings, namely a revolution speed of2000 rpm and a rotation speed of 800 rpm:

TABLE 4B Grinding of various API starting material and Temperaturemelting temp. grinding Before/After (° C.) media (° C.) ObservationMenthol, 20 balls, 24.3/31.5 (30 sec) begins to clump 5 g (31) 5 mm,24.3/32.5 (60 sec) (30 sec) spherical melting (60 sec) Sodium 20 balls,24.5/32.9 (30 sec) No visible reduction in Chloride, 5 mm, 24.5/48.3 (60sec) particle size. 5 g (801) spherical Sodium 20 balls, 24.5/45.1 (30sec) No visible reduction in Chloride, 5 mm, 24.5/58.5 (60 sec) particlesize. 5 g (801) cylindrical Gabapentin, 20 balls, 24.2/36.7 (30 sec)begins to clump 3 g (162) 5 mm, 24.2/46.8 (60 sec) (30 sec) cylindricalvery large clumps (60 sec) Gabapentin, 25 balls, 24.2/39.1 (30 sec) 1500rpm/600 rpm; 2 g (162) 10 mm, Container is hot to the cylindrical touch.Powder has not clumped together.

Other experiments were also made with 2 g of sodium chloride as startingmaterial and grinding media using various settings to more easilyvisually detect particle size reduction:

TABLE 4C Grinding of sodium chloride at various milling parametersTemperature Before/After grinding media (° C.) Observation 45 balls, 8mm, 23.4/28.7 (30 sec) 1000 rpm/400 rpm spherical 24.7/35.8 (60 sec)(rev./rot); Visual reduction in particle size without clumping. 45balls, 8 mm, 23.8/42.5 (30 sec) 1500 rpm/600 rpm spherical (rev./rot);Visual reduction in particle size without clumping. 25 balls, 10 mm,24.1/30.6 (30 sec) 1000 rpm/400 rpm cylindrical 24.2/39.5 (60 sec)(rev./rot); Visual reduction in particle size without clumping.

Other experiments were also made with Gabapentin 2 g as startingmaterial and grinding media using lower settings, namely a revolutionspeed of 1000 rpm and a rotation speed of 400 rpm:

TABLE 4D Grinding of Gabapentin Temperature Before/After grinding media(° C.) Observation 45 balls, 8 mm, 24.2/30.8 (30 sec) Visual reductionin particle size spherical 25.7/35.7 (60 sec) without clumping. 25balls, 10 mm, 24.4/25.6 (30 sec) Visually the powder does notcylindrical 23.6/25.5 (60 sec) look as micronized compared to tests withspheres.

These last results suggest that processing time parameters of 30 and 60seconds keep temperature below 40° C., which is below the typicaldegradation temperature for a thermally labile API.

Example 3

In this example, the following compounded pharmaceutical compositionswere prepared using the herein described superimposed revolution androtation movements using a planetary mixer (Mazerustar kk-300ss) withthe following dispersion parameters: processing time of 30 sec or 60 sec(either continuously or in two intervals of 30 seconds each), anddispersion speeds of 2000 rpm revolution and 800 rpm rotation. In somecases, a dye was added to the ingredients showing that the hereindescribed superimposed revolution and rotation movements can be used toalso disperse colorant within a compounded pharmaceutical composition.

TABLE 5 Ointment pharmaceutical composition 2% Mucirocin OintmentIngredient (NDC, Lot) Mupirocin (2545-03, 602996/B), Mineral Oil(0949-08, 38546/I), Medisca OleaBase Plasticized (2575-05, 601610/B) APIMelting Temperature (° C.) Mupirocin (77-78) Specific Gravity of BaseOleaBase Plasticized (0.85)

TABLE 6 Hormone replacement therapy (HRT) pharmaceutical composition(emulsion) 0.5% Estriol Vaginal Cream (Emulsion, 30 ml) Ingredient (NDC,Lot) Estriol (0732-03, 51222/C), Propylene Glycol (0510-08, 45008/B),VersaPro Cream (2529-08, 124989/B) API Melting Temperature (° C.)Estriol (288) Specific Gravity of Base VersaPro Cream (0.97) Temperaturebefore/after (° C.) 23.6/25.4 (30 sec.) 25.2/26.2 (30 sec., rest, 30sec.) 25.8/28.0 (60 sec)

TABLE 7 Hormone replacement therapy pharmaceutical composition (creambase) Estradiol 0.5 mg/ml, Estriol 2 mg/ml, Progesterone 150 mg/ml CreamBase Ingredient (NDC, Lot) Estradiol Estriol (0732-03, 51222/C),Progesterone (0043-08, 56345/B), Propylene Glycol (0510-08, 45008/B),HRT Cream (0701-08, 46213/K/B) API Melting Temperature (° C.) Estriol(288) Estradiol (178) Progesterone (129) Specific Gravity of BaseVersaPro Cream (0.97) Temperature before/after (° C.) 23.5/29.4 (30sec.) 29.1/29.7 (30 sec., rest, 30 sec.) 29.1/31.0 (60 sec.)

TABLE 8 Hormone replacement therapy pharmaceutical composition (creambase) Estradiol 0.5 mg/ml, Estriol 2 mg/ml, Progesterone 150 mg/ml, HRTCream Base Ingredient (NDC, Lot) Estradiol Estriol (0732-03, 51222/C),Progesterone (0043-08, 56345/B), Propylene Glycol (0510-08, 45008/B),HRT Cream (0701-08, 46213/K/B) API Melting Temperature (° C.) Estriol(288) Estradiol (178) Progesterone (129) Specific Gravity of Base HRTCream (0.98) Viscosity of Base HRT Cream (370 000 cP) Temperaturebefore/after (° C.) 23.5/29.4 (30 sec.) 29.1/29.7 (30 sec., rest, 30sec.) 29.1/31.0 (60 sec.)

TABLE 9 Gel composition Ibuprofen 5%, Menthol 3% Topical Gel(Suspension, 50 g) Ingredient (NDC, Lot) Ibuprofen (0299-05, 57128/A),Menthol (0521-05, 41612/B), Propylene Glycol (0510-08, 45008/B),VersaPro Gel (2636-05, 45712/P) API Melting Temperature (° C.) Ibuprofen(76), Menthol (41-44) Specific Gravity of Base VersaPro Gel (1.00)Viscosity of Base VersaPro Gel (1,000,000 cP) Temperature before/after(° C.) 23.0/27.3 (30 sec.) 22.9/26.0 (30 sec., rest, 30 sec.) 23.1/29.3(60 sec.)

TABLE 10 Gel composition Ibuprofen 5%, Menthol 3%, Medisca VersaPro GelBase Ingredient (NDC, Lot) Ibuprofen (0299-05, 57128/A), Menthol(0521-05, 41612/B), Propylene Glycol (0510-08, 45008/B), VersaPro Gel(2636-05, 45712/P) API Melting Temperature (° C.) Ibuprofen (76),Menthol (41-44) Specific Gravity of Base VersaPro Gel (0.984) Viscosityof Base VersaPro Gel (1,000,000 cP) Temperature before/after (° C.)23.2/24.8 (30 sec.) 24.8/25.7 (30 sec., rest, 30 sec.) 25.6/28.4 (60sec.)

TABLE 11 Pain pharmaceutical composition Gabapentin 6%, Ketoprofen 5%,Diclofenac 3%, Pentylene Glycol 3%, Ethoxy Diglycol 3%, Medisca VersaProCream Base. Ingredient (NDC, Lot) Gabapentin (2461-05, 57807/I),Ketoprofen (0078-05, 56561/B), Diclofenac (2552-08, 44843/B), PentyleneGlycol (2752-08, 50713/A), Ethoxy Diglycol (1903-05, 54500/B), VersaProCream (2529-08, 124989/B) Red dye API Melting Temperature (° C.)Gabapentin (162-166) Ketoprofen (94) Diclofenac (283-285) SpecificGravity of Base VersaPro Cream (0.99) Temperature before/after (° C.)23.3/24.9 (30 sec.) 24.7/25.5 (30 sec., rest, 30 sec.) 25.4/26.6 (60sec.)

In the particular pain pharmaceutical composition described in Table 11,the red dye was added on top of the ingredients. Following thedispersion of the ingredients, the resulting mixture had a substantiallyhomogeneous pink color as early as 30 sec.

TABLE 12 Amlodipine Suspension Amlodipine 1 mg/mL, Medisca Oral MixIngredient (NDC, Lot) Amlodipine (2734-blk, 49214, 04/2018), MediscaOral Mix (2512-08, I102/A, 09/2015) Red dye API Melting Temperature (°C.) Amlodipine (178-179) Specific Gravity of Base Oral Mix (1.1202)Viscosity of Base Oral Mix (300 cP) Temperature before/after (° C.)15.8/16.0 (30 sec.) 16.0/16.2 (30 sec., rest, 30 sec.) 16.2/17.0 (60sec.)

In this particular example of a pharmaceutical suspension beingdispersed in presence of a red dye, the dye was placed on top of theingredients. Following the dispersion of the ingredients, the resultingmixture had a substantially homogeneous pink color as early as 30 sec.

Example 4

In this example, the following compounded pharmaceutical compositionswere prepared using the herein described superimposed revolution androtation movements m a planetary mixer (Mazerustar kk-300ss). Thedispersing time and the dispersing speed parameters were modified, and adispersing assessment was made, as indicated in the following tables.Note that the rotation speed (rpm) was kept at a value of 40% of therevolution speed (rpm).

TABLE 13 Cellulose, NF (Microcrystalline) Ingredient (NDC, Cellulose, NF(0567-08, 27688/B) Lot) Weight (g) 50 25 Temperature before/ 29.3 (1000rpm/120 sec) 33.0 (1500 rpm/60 sec) after (° C.) when 35.3 (1500 rpm/120sec) 30.4 (1500 rpm/30 sec) room temperature at 31.4 (1500 rpm/60 sec) 24° C. Mixing assessment 1000 rpm/120 sec + 1500 rpm/60 sec ++ 1500rpm/120 sec + 1500 rpm/30 sec ++

TABLE 14 Lactose, NF (Monohydrate) at variable dispersing timeIngredient (NDC, Lot) Lactose, NF (Monohydrate) (0315-08, 600938/C and603118/B) Weight (g) 50 Temperature after Dispersing (° C.) when roomRevolution time temperature at Mixing (rpm) (sec) 24° C. assessment 1000150 29.7 ++ 1000 120 29.4 ++ 1000 90 28.0 ++ 1000 60 28.0 ++ 500 3025.2 + 1000 30 26.7 ++ 1500 30 30.9 ++ 2000 30 40.5 ++

TABLE 15 Lactose, NF (Monohydrate) at 180 sec dispersing time Ingredient(NDC, Lot) Lactose, NF (Monohydrate) (0315-08, 600938/C and 603118/B)Red dye Dispersing time (sec) 180 Temperature after (° C.) when roomWeight Revolution temperature Mixing (g) (rpm) at 24° C. assessment 25500 24.6 − 1000 29.6 ++ 1500 38.1 ++ 2000 51.5 ++ 50 500 26.7 − 100032.1 ++ 1500 43.8 ++ 2000 63.2 ++ 60 500 * 1000 31.1 − 1500 44.0 ++ 2000** 75 500 * 1000 27.9 ++ 1500 37.2 ++ 2000 55.5 ++ In the aboveresults, * means that the G forces were observed as being insufficientto achieve a mix whereas ** means that the temperature exceeded thepre-determined threshold temperature of 45° C. for thermally labile API.In this example, a red dye was used to qualitatively assess thedispersion.

In the above results, * means that the G forces were observed as beinginsufficient to achieve a mix whereas ** means that the temperatureexceeded the pre determined threshold temperature of 45° C. forthermally labile API. In this example, a red dye was used toqualitatively assess the dispersion.

TABLE 16 Capsublend at 60 sec dispersing time Ingredient (NDC, Lot)Capsublend-P (2594-08, 58203/C) Capsublend-S (2593-05, 51997/B and38893/B) Red dye Dispersing time (sec) 60 Temperature after (° C.) whenroom Weight Revolution Rotation temperature Mixing (g) (rpm) (rpm) at24° C. assessment 25 400 160 25.0 − 1000 400 27.5 − 1500 600 31.1 − 2000800 37.5 ++ 50 400 160 25.1 − 1000 400 27.9 − 1500 600 32.4 − 2000 80041.9 ++

In this example, the following compounded pharmaceutical compositionsincluding 3 different APIs were prepared using the herein describedsuperimposed revolution and rotation movements, or using an Unguator™ ascontrol comparative blade mixing device (Gako International), with thefollowing ingredients:

TABLE 17 Ingredients % g/ml NDC Lot Diclofenac Sodium 3.0 7.5, 7.95, 7.82705-05 44843/B Gabapentin 6.0 15, 15.9, 15.6 603948/A Ketoprofen 5.012.5, 13.25, 13 602182/F Pentylene Glycol 3.0 7.5, 6.5, 6.25 2752-08507131/A Ethoxy Diglycol 3.0 7.5, 6.5, 6.25 54500/B VersaPro Cream QS to250 g 188.5, 265, 260 605062/A Base

Die superimposed revolution and rotation movements parameters were: 2000rpm for 30 sec (samples 1-3). The parameters for the Unguator™ controlcomparative blade mixing device (samples 4-5) were: speed 5 for 120 sec(sandwich protocol). Each of the resulting composition was thenseparated in top, middle and bottom layers and the concentration of eachAPI in each layer was measured with HPLC. Hie average concentration ([]), the standard deviation (SD) and the relative standard deviation (%RSD) were calculated for each API. The results are shown in thefollowing Table:

TABLE 17A Results for a composition including 3 API Diclofenac 3%Gabapentin 6% Ketoprofen 5% Assay [ ] SD % RSD [ ] SD % RSD [ ] SD % RSD1 2.8 0.000 0.0% 5.9 0.047 0.8% 4.9 0.125 2.5% 2 2.8 0.047 1.7% 5.80.000 0.0% 4.9 0.082 1.7% 3 2.7 0.000 0.0% 5.7 0.000 0.0% 4.8 0.047 1.0%4 2.8 0.125 4.4% 5.6 0.262 4.7% 4.9 0.283 5.8% 5 2.7 0.094 3.5% 5.40.262 4.8% 4.7 0.216 4.6% 6 2.8 0.082 2.9% 5.5 0.170 3.1% 4.8 0.094 2.0%

These results show that the average % RSD is significantly lower whenusing the superimposed revolution and rotation movements relative to theUnguator™ control comparative blade mixing device. The inventors werealso able to consistently (in over 80% of tire cases) obtain for a givenAPI less than 3% RSD, suggesting a significant homogeneity in thecompositions made as well as more reproducible results (i.e., lessvariations from one composition to another). In contrast, the Unguator™control comparative blade mixing device consistently (in over 80% of thecases) showed higher and variable % RSD for a given API, suggesting lesshomogeneous compositions and less reproducible results.

Example 6

In this example, the following compounded pharmaceutical compositionsincluding 4 different APIs were prepared using the herein describedsuperimposed revolution and rotation movements, with the followingingredients:

TABLE 18 Ingredients Ingredients % g/ml NDC Lot Baclofen, USP 2.0 4.00388-04 112624/E Bupivacaine HCl, USP 2.5 5.0 0524-04 122720/ICyclobenzaprine HCl, USP 6.0 12.0 0395-05 115114/E Diclofenac Sodium,USP 10.0 20.0 2705-05 118032/I Ethoxy Diglycol 3.5 7.0 1903-05 119825/DPentylene Glycol 3.5 7.0 2752-08 122018/B VersaPro Cream Base 72.5 145.02529-08 121176/D

The superimposed revolution and rotation movements parameters were: 2000rpm for 30 sec (samples 4-6). The parameters for due Unguator™ controlcomparative blade mixing device (samples 1-3) were: speed 5 for 120 sec(sandwich protocol). Each of the resulting composition was thenseparated in top, middle and bottom layers and the concentration of eachAPI in each layer was measured with HPLC. The average concentration ([]), the standard deviation (SD) and the relative standard deviation (%RSD) were calculated for each API. The results are shown in thefollowing Table:

TABLE 19 Results for a composition including 4 API Baclofen, 2%Bupivicaine, 2.5% Cyclobenzaprine, 6% Diclofenac, 10% Assay [ ] SD % RSD[ ] SD % RSD [ ] SD % RSD [ ] SD % RSD 1 2.0 0.265 13%  2.1 0.265 13% 5.4 0.586 11%  9.5 1.079 11%  2 2.0 0.058 3% 2.1 0.100 5% 5.3 0.208 4%9.3 0.361 4% 3 1.9 0.306 16%  2.0 0.306 15%  5.1 0.794 16%  9.1 1.40115%  4 2.1 0.058 3% 2.2 0.058 3% 5.6 0.208 4% 9.9 0.321 3% 5 2.1 0.1005% 2.2 0.115 5% 5.5 0.306 6% 9.6 0.586 6% 6 1.9 0.000 0% 2.1 0.000 0%5.2 0.153 3% 9.1 0.153 2%

These results show that the average % RSD is significantly lower whenusing the superimposed revolution and rotation movements relative to theUnguator™ control comparative blade mining device, lire inventors werealso able to consistently (in over 80% of the cases) obtain for a givenAPI less than 3% RSD, suggesting a significant homogeneity in thecompositions made as well as more reproducible results (i.e., lessvariations from one composition to another). In contrast, the Unguator™control comparative blade mixing device consistently (in over 80% of diecases) showed higher and variable % RSD for a given API, suggesting lesshomogeneous compositions and less reproducible results.

Example 7

In this example, a jar container having a certain internal ratio wasused to disperse ingredients using the herein described superimposedrevolution and rotation movements. The jar is equipped with an adaptorto fit the jar container into a receiving basket of a planetary mixer.The ingredients used a pharmaceutically acceptable carrier, excipient ordiluent, Versapro Cream Base and a red dye, as a tracer. The amount ofVersapro added into the container was sufficient to reach the top of theviewing window on the jar container (MD line of containers, from MediscaPharmaceutique). Note that the rotation speed (rpm) was kept at a valueof 40% of the revolution speed (rpm).

TABLE 20 Results for Versapro Cream in MD jar container Volume ofVersapro Cream Revolution Temperature (° C.), Base (rpm) TimeObservation 30 ml 400 23.3 (30 sec) Dye reached halfway down (30 sec)23.7 (60 sec) Dye moved 5 mm further (60 sec) 24.0 (90 sec) Dye moved 2mm further (90 sec) 24.3 (120 sec) Dye 2 mm from bottom. (120 sec) 100024.7 (30 sec) Dye reached the bottom, homogeneous mix 25.2 (120 sec) (30and 120 sec) 1500 25.9 (120 sec) Dye reached the bottom, homogeneous mix2000 24.0 (30 sec) Dye reached the bottom, homogeneous mix 26.5 (120sec) (30 and 120 sec) 50 ml 400 23.7 (120 sec) 1000 24.0 (30 sec) Dyereached the bottom, homogeneous mix 25.7 (120 sec) (30 and 120 sec) 150023.9 (30 sec) Dye reached the bottom, homogeneous mix 25.7 (120 sec) (30and 120 sec) 2000 Slight leakage past the piston at all tested times,except for 120 sec where it is severe leakage 80 ml 400 23.6 (120 sec)Dye reached the bottom, homogeneous mix 1000 23.8 (30 sec) Dye reachedthe bottom, homogeneous mix 24.6 (120 sec) 1500 23.9 (30 sec) Dyereached the bottom, homogeneous mix 25.8 (120 sec) 2000 27.2 (120 sec)Dye reached the bottom, homogeneous mix

Safe dispersing parameters so as to avoid leakage, thus, appear to be1500 rpm at 0.5 min, and are applicable to all sizes of the MD line ofjar containers.

Example 8

In this example, a 6.5 ml syringe container (Medisca Pharmaceutique) wasused to disperse ingredients using the herein described superimposedrevolution and rotation movements. The syringe container is equippedwith an adaptor to fit the syringe container into a receiving basket ofthe planetary mixer. The ingredients used were a pharmaceuticallyacceptable carrier, excipient or diluent, Versapro Cream Base and a reddye, as a tracer. The amount of Versapro added into the syringecontainer was of 6.5 g. The dispersed cream was then visually assessedfor entrapped air bubbles levels and red dye homogeneity dispersion.Note that the rotation speed (rpm) was kept at a value of 40% of therevolution speed (rpm).

TABLE 21 Results for Versapro Cream in syringe container Revolution Time(rpm) (sec) Observation 500 120 Dye failed to travel down. No noticeablechange in air bubble size or shape. 1000 120 Dye failed to travel down.Air bubbles size has decreased but still large number of bubbles visible(mostly non-uniform in size and shape). 1500 30 Dye moved down 2 cm. Airbubbles size has decreased and shape of air bubbles is more uniform. 60Dye moved down a further 0.5 cm. Layers of colour near the centersuggesting heterogeneous mixing. 90 Dye moved down a further 0.5 cm.Layers of colour near the center suggesting heterogeneous mixing. 120Dye stopped at center cartridge. Heterogeneous mix 2000 30 Dye moveddown effectively (2.7 cm). Fewer air bubbles, size has also decreased.Less bubble towards the top. 60 Dye moved down an additional 1-1.5 cm.Mixing flow visible. Layers of distinct shades of pink indicatenon-uniform mixing near the center. Slightly more uniform bubble sizeand shape. No significant change in number of bubbles. Temperature:28.5° C. 90 Dye moved down (1 cm above the bottom of the cartridge).Mixing flow visible. Top layer (darker pink) has increased, more uniformin the middle compared to before, however, layers still visible. Nosignificant Change in size, shape or number of bubbles. Temperature:29.7 C.° 120 Dye has reached bottom of cartridge completely. Mixing flowvisible. Layers are less prevalent, color is more uniform throughout.Noticeable change in number of bubbles. Size has slightly decreased.Temp: 31.2 C.°

Similar results were obtained when dispersing in a syringe container of5.0 ml (Medisca Pharmaceutique, Montreal, Canada).

Example 9

In this example, various pharmaceutically acceptable excipients,carriers or diluents in solid or semi-solid form (i.e., more or lessviscous, so long as it cannot be poured like a liquid) were submitted tothe herein described superimposed revolution and rotation movements inan attempt to obtain a reversible melt. The dispersing parameters usedwere 2000 rpm revolution and 800 rpm rotation.

TABLE 22 Melting of excipient, carrier or diluent Excipient, carrier ordiluent Observation VersaPro ™ Cream 300 sec dispersing resulted in atemperature of 31.6° C., appears as a cream OleaBase ™ Plastisized 240sec dispersing resulted in a temperature of 38.2° C. Ointment Base 300sec dispersing resulted in a temperature of 34.2° C., the base becamevery soft and liquid. There is a major change in consistency andtexture. PLO Gel Mediflo ™ 30 210 sec dispersing resulted in atemperature of 39.1° C., the gel appears like a cream, not a pourableliquid PolyPeg Suppository Base 300 sec dispersing resulted in atemperature of 51.1° C., the base appears like a cream, not a pourableliquid SPG Supposi-Base ™ 300 sec dispersing resulted in a temperatureof 34.1° C., the base appears like a cream, not a pourable liquid GumBase Gelatin 180 sec dispersing resulted in a temperature of 55.1° C.,the initial cube shaped gelatin forms melt into a pourable liquid.

The experiment was repeated in different planetary mixer devices, as perthe following paragraphs.

TABLE 22.1 Mazerustar KK-300SS comparison of gelatin gum base chunk sizeTest 10 Test 16 Lot Number 617221/A 617221/A Mass (gram) 50.02 50.07 RPM2000 2000 G Force 284 284 Time (seconds) 180 180 Temperature Before (°C.) 23.8 25.5 Temperature After (° C.) 59.6 57.7 ΔT (° C.) 35.8 32.2Observation fully melted not fully melted as little blocks cut stuck tothe top

FIG. 33 shows a typical gum base gelatin particle unaltered from themanufacturers' container (left) and a plurality of these particlescontained in due dispersion jar (right). The block has a maximal extentsize of about 1 inch.

FIG. 34 shows gum base gelatin particles which have been cut down fromthe initial size present in the manufacturers' container (left) and aplurality of these parades contained in the dispersion jar (right). Thecut down parades have a size of less than about 0.5 inch.

A two (2) decimal place balance was used to weigh the gelatin gum base.During the weighing operations, a plastic jar was placed on the balanceand tared. During the first experiment run, 50 grams was processedunaltered. During the second experiment ran, the 50 grams of gelatin gumbase was minced into smaller pieces. The initial temperature wasrecorded using a digital thermometer with stainless steel probe byinserting the tip inside of the gum base gelatin before being insertedinside the planetary mixer. The final temperature was measured once thedispersion process was completed, by inserting and swirling thestainless steel probe in the gelatin in order to avoid coagulation asmuch as possible.

The herein described superimposed revolution and rotation movements wasused to melt the gelatin gum base and the process parameters/resultsobtained were compared to those performed/obtained when using a hotplate. The melted gelatin gum base was assessed by measuring thetemperature before and after the melting process by using a digitalthermometer with a stainless-steel probe. FIG. 35A-35E shows examples ofgum base that completely melted (35A), partially melted (35B, 35C and35D), and did not melt (35E).

TABLE 22.2 Mazerustar KK-300SS - 25 gram, 180 seconds, variable G ForceTest 3 Test 2 Test 4 Lot Number 617221/A 617221/A 617221/A Mass (gram)25.00 25.20 25.03 RPM 1600 1800 2000 G Force 182 230 284 Time (seconds)180 180 180 Temperature Before (° C.) 24.3 24.3 24.3 Temperature After(° C.) 50.5 49.1 51.6 ΔT (° C.) 26.2 24.8 27.3 Observation partiallymelted completely completely melted melted

TABLE 22.3 Mazerustar KK-300SS - 50 gram, 180 seconds, variable G ForceTest 7 Test 9 Test 10 Lot Number 617221/A 617221/A 617221/A Mass (gram)50.04 50.01 50.02 RPM 1600 1800 2000 G Force 182 230 284 Time (seconds)180 180 180 Temperature Before (° C.) 24.3 24.0 23.8 Temperature After(° C.) 50.7 56.1 59.6 ΔT (° C.) 26.4 32.1 35.8 Observation partiallymelted completely completely melted melted

TABLE 22.4 Mazerustar KK-300SS - 75 gram, 180 seconds, variable G ForceTest 8 Test 11 Test 12 Lot Number 617221/A 617221/A 617221/A Mass (gram)75.03 75.03 75.03 RPM 1600 1800 2000 G Force 182 230 284 Time (seconds)180 180 180 Temperature Before (° C.) 23.6 23.4 23.3 Temperature After(° C.) 30.6 30.3 56.4 ΔT (° C.) 7.0 6.9 33.1 Observation not melted notmelted completely melted

TABLE 22.5 Mazerustar KK-300SS - 75 gram, constant G Force, variabletime Test 12 Test 18 Test 17 Lot Number 617221/A 617221/A 617221/A Mass(gram) 75.03 75.01 75.00 RPM 2000 2000 2000 G Force 284 284 284 Time(seconds) 180 300 450 Temperature Before (° C.) 23.3 25 23.7 TemperatureAfter (° C.) 56.4 60.9 61.9 ΔT (° C.) 33.1 35.9 38.2 Observationcompletely completely completely melted melted melted

TABLE 22.6 Mazerustar KK-300SS - Constant G Force, 180 seconds, variablemass Test 4 Test 10 Test 12 Lot Number 617221/A 617221/A 617221/A Mass(gram) 25.03 50.02 75.03 RPM 2000 2000 2000 G Force 284 284 284 Time(seconds) 180 180 180 Temperature Before (° C.) 24.3 23.8 23.3Temperature After (° C.) 51.6 59.6 56.4 ΔT (° C.) 27.3 35.8 33.1Observation completely completely completely melted melted melted

TABLE 22.7 Mazerustar KK-300SS - Constant G Force, 300 seconds, variablemass Test 20 Test 19 Test 18 Test 13 Lot Number 617221/A 617221/A617221/A 617221/A Mass (gram) 25.04 50.03 75.01 100.03 RPM 2000 20002000 2000 G Force 284 284 284 284 Time (seconds) 300 300 300 300 Temp.Before 24.3 24.1 25 23.4 (° C.) Temp. After 54.2 60.4 60.9 60.1 (° C.)ΔT (° C.) 29.9 36.3 35.9 36.7 Observation completely completelycompletely completely melted melted melted melted

TABLE 22.8 Mazerustar KK-400 - 75 gram, Constant time, variable G ForceTest 14 Test 13 Test 12 Lot Number 617221/A 617221/A 617221/A Mass(gram) 75.02 75.02 75.03 Revolution Setting # 7 8 9 Rotation Setting # 78 9 RPM 1058 1218 1340 G Force 170 226 273 Time (seconds) 450 450 450Temperature Before (° C.) 24.5 24.5 24.3 Temperature After (° C.) 34.563.8 66.3 ΔT (° C.) 10.0 39.3 42.0 Observation not melted completelycompletely melted melted

TABLE 22.9 Mazerustar KK-400 - 25 gram, Constant G Force, variable timeTest 18 Test 3 Test 5 Test 1 Lot Number 617221/A 617221/A 617221/A617221/A Mass (gram) 25.00 25.00 25.05 25.00 Revolution Setting # 9 9 99 Rotation Setting # 9 9 9 9 RPM 1340 1340 1340 1340 G Force 273 273 273273 Time (seconds) 180 300 450 600 Temp. Before (° C.) 23.5 24.4 24.724.3 Temp. After (° C.) 32.2 32.6 56.3 61.8 ΔT (° C.) 8.7 8.2 31.6 37.5Observation not melted not melted completely completely melted melted

TABLE 22.10 Mazerustar KK-400 - 50 gram, Constant G Force, variable timeTest 19 Test 2 Test 8 Test 11 Lot Number 617221/A 617221/A 617221/A617221/A Mass (gram) 50.06 50.00 50.04 50.01 Revolution Setting # 9 9 99 Rotation Setting # 9 9 9 9 RPM 1340 1340 1340 1340 G Force 273 273 273273 Time (seconds) 180 300 450 600 Temp. Before (° C.) 24.0 24.3 23.924.5 Temp. After (° C.) 39.9 44.8 64.2 67.5 ΔT (° C.) 15.9 20.5 40.343.0 Observation partially partially completely completely melted meltedmelted melted

TABLE 22.11 Mazerustar KK-400 - 75 gram, Constant G Force, variable timeTest 10 Test 6 Test 12 Test 15 Lot Number 617221/A 617221/A 617221/A617221/A Mass (gram) 75.06 75.01 75.03 75.02 Revol. Setting # 9 9 9 9Rotation Setting # 9 9 9 9 RPM 1340 1340 1340 1340 G Force 273 273 273273 Time (seconds) 180 300 450 600 Temp. Before 23.6 25.2 24.3 24.4 (°C.) Temp. After 33.5 65.6 66.3 69.5 (° C.) ΔT (° C.) 9.9 40.4 42.0 45.1Observation not melted completely completely completely melted meltedmelted

TABLE 22.12 Mazerustar KK-400 - 100 gram, Constant G Force, variabletime Test 22 Test 16 Test 20 Lot Number 617221/A 617221/A 617221/A Mass(gram) 100.09 100.02 100.00 Revolution Setting # 9 9 9 Rotation Setting# 9 9 9 RPM 1340 1340 1340 G Force 273 273 273 Time (seconds) 300 450600 Temperature Before (° C.) 23.4 25.0 23.6 Temperature After (° C.)65.0 69.6 68.7 ΔT (° C.) 41.6 44.6 45.1 Observation completelycompletely completely melted melted melted

TABLE 22.13 Mazerustar KK-400 - Constant G Force, 180 seconds, variablemass Test 18 Test 19 Test 10 Lot Number 617221/A 617221/A 617221/A Mass(gram) 25.00 50.06 75.06 Revolution 9 9 9 Setting # Rotation 9 9 9Setting # RPM 1340 1340 1340 G Force 273 273 273 Time 180 180 180(seconds) Temperature 23.5 24.0 23.6 Before (° C.) Temperature 32.2 39.933.5 After (° C.) ΔT (° C.) 8.7 15.9 9.9 Observation not meltedpartially not melted melted

TABLE 22.14 Mazerustar KK-400 - Constant G Force, 300 seconds, variablemass Test 3 Test 2 Test 6 Test 22 Lot Number 617221/A 617221/A 617221/A617221/A Mass (gram) 25.00 50.00 75.01 100.09 Revolution 9 9 9 9 Setting# Rotation 9 9 9 9 Setting # RPM 1340 1340 1340 1340 G Force 273 273 273273 Time 300 300 300 300 (seconds) Temp. 24.4 24.3 25.2 23.4 Before (°C.) Temp. 32.6 44.8 65.6 65 After (° C.) ΔT (° C.) 8.2 20.5 40.4 41.6Observation not melted partially com- com- melted pletely pletely meltedmelted

TABLE 22.15 Mazerustar KK-400 - Constant G Force, 450 seconds, variablemass Test 5 Test 8 Test 12 Test 16 Lot Number 617221/A 617221/A 617221/A617221/A Mass (gram) 25.05 50.04 75.03 100.02 Revolution 9 9 9 9 Setting# Rotation 9 9 9 9 Setting # RPM 1340 1340 1340 1340 G Force 273 273 273273 Time 450 450 450 450 (seconds) Temp. 24.7 23.9 24.3 25.0 Before (°C.) Temp. 56.3 64.2 66.3 69.6 After (° C.) ΔT (° C.) 31.6 40.3 42 44.6Observation com- com- com- com- pletely pletely pletely pletely meltedmelted melted melted

TABLE 22.16 Mazerustar KK-400 - Constant G Force, 600 seconds, variablemass Test 1 Test 11 Test 15 Test 20 Test 17 Lot Number 617221/A 617221/A617221/A 617221/A 617221/A Mass (gram) 25.00 50.01 75.02 100.00 151.03Revolution 9 9 9 9 9 Setting # Rotation 9 9 9 9 9 Setting # RPM 13401340 1340 1340 1340 G Force 273 273 273 273 273 Time 600 600 600 600 600(seconds) Temperature 24.3 24.5 24.4 23.6 23.4 Before (° C.) Temperature61.8 67.5 69.5 68.7 67.5 After (° C.) ΔT (° C.) 37.5 43 45.1 45.1 44.1Observation com- com- com- com- com- pletely pletely pletely pletelypletely melted melted melted melted melted

TABLE 22.17 Mazerustar KK-1000 - 200 grams, 450 seconds, variable GForce Test 7 Test 6 Test 2 Lot Number 608721/A & 608721/A 617221/A605082/A Mass (gram) 200.01 200.02 200.07 Revolution 7 8 9 Setting #Rotation 7 8 9 Setting # RPM 770 860 950 G Force 149 186 227 Time 450450 450 (seconds) Temperature 23.2 22.8 24.9 Before (° C.) Temperature57.5 60.6 68 After (° C.) ΔT (° C.) 34.3 37.8 43.1 Observation com- com-com- pletely pletely pletely melted melted melted

TABLE 22.18 Mazerustar KK-1000- 200 grams, Constant G Force, variabletime Test 9 Test 4 Test 2 Test 5 Lot Number 605082/A 617221/A 617221/A617221/A Mass (gram) 200.15 200.20 200.07 200.05 Revolution 9 9 9 9Setting # Rotation 9 9 9 9 Setting # RPM 950 950 950 950 G Force 227 227227 227 Time 180 300 450 600 (seconds) Temperature 23.0 24.5 24.9 24.9Before (° C.) Temperature 63.6 63.8 68.0 72.8 After (° C.) ΔT (° C.)40.6 39.3 43.1 47.9 Observation com- com- com- com- pletely pletelypletely pletely melted melted melted melted

TABLE 22.19 Mazerustar KK-1000- Constant G Force, 450 seconds, variablemass Test 1 Test 2 Test 3 Test 8 Lot Number 617221/A 617221/A 617221/A608721/A Mass (gram) 100.05 200.07 300.09 525.53 Revolution 9 9 9 9Setting # Rotation 9 9 9 9 Setting # RPM 950 950 950 950 G Force 227 227227 227 Time 450 450 450 450 (seconds) Temperature 24.9 24.9 24.7 23.4Before (° C.) Temperature 33.0 68.0 71.2 67.7 After (° C.) ΔT (° C.) 8.143.1 46.5 44.3 Observation not melted com- com- com- pletely pletelypletely melted melted melted

Hot Plate

TABLE 22.20 Hot Plate Test 1 Test 2 Test 3 Lot Number 10810/B 10810/B608721/A Mass (gram) 50.325 70.273 100.090 Time (seconds) 559 790 1059Temperature Before (° C.) 24.5 24.5 24.5 Temperature After (° C.) 59.159.6 58.4 ΔT (° C.) 34.6 35.1 33.9 Observation com- com- com- pletelypletely pletely melted melted melted

Material and Methods Hot Plate

A water bath was set with a water temperature of 65° C. A hot plateThermos Scientific Cimarec™ model SP131325 was used. A beaker of sizePyrex™ number 1003 with capacity 1000 ml, 4 in diameter and 6 in inheight, was used to contain the water. A beaker of size Veegee™ Glassconumber 20229 with capacity 600 ml, 3.5 in diameter and 5 in in height,was used to contain the gelatin. The gelatin gum base was placed in themelting beaker and the timer was started. The water temperature of 65°C. was maintained while briefly mixing every 3 minutes. Time wasrecorded once all gelatin cubes had melted. Final temperature of meltedgelatin gum base was recorded. This experimental assessment wasreproduced for 50, 75 and 100 grams.

Mazerustar KK-300SS, KK-400 and KK-1000

A two (2) decimal place balance was used to weight the gelatin gum base.During the weighing operations, a plastic jar was placed on the balanceand tared. Various amounts of gelatin gum base were tested due to thevarying capacities of the different planetary mixers, the weights of 25,50, 75, 100, 120, 150, 200, 300 and 500 grams were selected. Thetemperature was recorded using a digital thermometer with stainlesssteel probe by insetting the tip inside of the gelatin gum base. Thefinal temperature was measured by repeating the process and swirling thestainless steel probe as to avoid coagulation as much as possible.

Mazerustar KK-300SS

Parameters of 180 seconds time period in combination with 25, 50 and 75grams were used for increasing G Force and RPM. For the MazerustarKK-300SS: 182 G Force corresponds to 1600 RPM; 230 G Force correspondsto 1800 RPM; and 284 G Force corresponds to 2000 RPM.

Parameters of G Force of 284 (2000 RPM) in combination with 75 gramswere used for increasing the time of melting in the Mazerustar. For theMazerustar KK-300SS times of 180, 300 and 450 seconds were used.

Parameters of G force of 284 (2000 RPM) in combination with 180 secondswere used for increasing the mass of melting in the Mazerustar. For theMazerustar KK-300SS mass of 25, 50 and 75 grams were used.

Parameters of G force of 284 (2000 RPM) in combination with 300 secondswere used for increasing the mass of melting in the Mazerustar. For theMazerustar KK-300SS mass of 25, 50, 75 and 100 grams were used.

Mazerustar KK-400

Parameters of 450 seconds time period in combination with 75 grams wereused for increasing G Force and RPM. For the Mazerustar KK-400: 170 GForce corresponds to 1058 RPM; 226 G Force corresponds to 1218 RPM; and273 G Force corresponds to 1340 RPM.

Parameters of G Force of 273 (1340 RPM) in combination with 25, 50 and75 grams were used for increasing the time of melting in the Mazerustar.For the Mazerustar KK-400 times of 180, 300, 450 and 600 seconds wereused.

Parameters of G Force of 273 (1340 RPM) in combination with 100 gramswere used for increasing the time of melting in the Mazerustar. For theMazerustar KK-400 times of 300, 450 and 600 seconds were used.

Parameters of G force of 273 (1340 RPM) in combination with 180 secondswere used for increasing the mass of melting in the Mazerustar. For theMazerustar KK-400 mass of 25, 50 and 75 grams were used.

Parameters of G force of 284 (2000 RPM) in combination with 300 and 450seconds were used for increasing the mass of melting in the Mazerustar.For the Mazerustar KK-400 mass of 25, 50, 75 and 100 grams were used.

Parameters of G force of 284 (2000 RPM) in combination with 600 secondswere used for increasing the mass of melting in the Mazerustar. For theMazerustar KK-400 mass of 25, 50, 75, 100 and 150 grams were used.

Mazerustar KK-1000

Parameters of 450 seconds time period in combination with 200 grams wereused for increasing G Force and RPM. For the Mazerustar KK-1000: 149 GForce corresponds to 770 RPM; 186 G Force corresponds to 860 RPM; and227 G Force corresponds to 950 RPM.

Parameters of G Force of 227 (950 RPM) in combination with 200 gramswere used for increasing the time of melting in the Mazerustar. For theMazerustar KK-1000 times of 180, 300, 450 and 600 seconds were used.

Parameters of G force of 227 (950 RPM) in combination with 450 secondswere used for increasing the mass of melting in the Mazerustar. For theMazerustar KK-1000 mass of 100, 200, 300 and 500 grams were used.

Results and Discussion

The following can be deduced from due results reported in tables 20 and20.1 to 20.20 as well as in FIGS. 36-38.

The gelatin particles melted as the planetary motion induced frictionbetween the particles and the inside surfaces of the jar. By nature,gelatin gum base has an adhesive surface. The gelatin gum base chunkvolume and mass increased proportionally. However, the surface areaadhering to the plastic of the same chunk of gelatin gum base alsoincreased but at a lower rate than the mass. The smaller the mass of thegelatin chunk, the more difficulty the planetary mixer had of dislodgingthe mass of gelatin stuck on the wall and, thus, not being able to melt.

The results show that that there was a direct correlation betweenmelting and the planetary mixer's G Force/RPM speed, time and mass ofgum base gelatin. The final temperature of the melted substanceincreased as the G Force/RPM speed increased and the time increased. Thefinal temperature of the melted substance followed a quadratic function,where a minimal and a maximal mass can be used to melt the gelatin gumbase.

Example 10

In this example, an Unguator cartridge was used to disperse ingredientsthe herein described superimposed revolution and rotation movements. Thecartridge is fitted with an adaptor to fit the Unguator cartridge into areceiving basket of the planetary mixer. The ingredients used were apharmaceutically acceptable carrier, excipient or diluent, VersaproCream Base and a red dye, as a tracer. The amount of Versapro added intothe Unguator cartridge was the nominal value recommended by the Unguatormanufacturer. The dispersed cream was then visually assessed for red dyehomogeneity dispersion. Note that the rotation speed (rpm) was kept at avalue of 40% of the revolution speed (rpm).

TABLE 23 Versapro in Unguator cartridge Volume of Unguator revolutionTemperature cartridge (rpm) (° C.), Time Observation 15 ml 400 25.1 (120sec) Not completely homogeneous mix, very light color in the middle.1000 23.7 (30 sec) Dye reached the bottom, homogeneous mix (30 and 25.7(120 sec) 120 sec) 1500 24.1 (30 sec) Dye reached the bottom,homogeneous mix (30 and 26.2 (120 sec) 120 sec) 2000 No leakage beyondthe piston. However, jar came loose from the lid and cream spilled out.20 ml 400 24.1 (120 sec) Not completely homogeneous, lighter color inthe middle (30 sec). Dye reached the bottom, homogeneous mix and uniformcolor. (120 sec) 1000 25.8 (30 sec) Dye reached the bottom, homogeneousmix and 25.8 (120 sec) uniform color (30 sec and 120 sec) 1500 25.8 (30sec) Dye reached the bottom, homogeneous mix and 26.3 (120 sec) uniformcolor (30 sec and 120 sec) 2000 No leakage beyond the piston. However,jar came loose and detached from the lid and cream spilled out. 30 ml400 Dye did not reach the bottom, not a homogeneous mix. (30 sec and 120sec) 1000 23.2 (30 sec) Dye reached the bottom, homogeneous mix (30 sec24.6 (120 sec) and 120 sec) 1500 23.1 (30 sec) Dye reached the bottom,homogeneous mix (30 sec) No leakage beyond the piston. However, jar cameloose and detached from the lid and cream spilled out. (60 sec) 2000 — —50 ml 400 23.9 (120 sec) Dye did not reach the bottom, not a homogeneousmix (30 sec) Dye reached the bottom, homogeneous mix and uniform color.(120 sec) 1000 23.1 (30 sec) Dye reached the bottom, homogeneous mix (30sec 25.1 (120 sec) and 120 sec) 1500 No leakage beyond the piston.However, jar came loose and detached from the lid and cream spilled out.(30 sec) 100 ml  400 23.1 (120 sec) Dye did not reach the bottom, not ahomogeneous mix (30 sec) Dye reached the bottom, homogeneous mix anduniform color. (120 sec) 1000 24.2 (30 sec) Dye reached the bottom,homogeneous mix (30 sec) 24.2 (120 sec) 1500 23.2 (30 sec) Dye reachedthe bottom, homogeneous mix and uniform color. However, jar had becomeslightly loose from the lid. (30 sec) No leakage beyond the piston.However, jar came loose and detached from the lid and cream spilled out.(60 sec)

Safe dispersing parameters so as to avoid leakage, thus, appear to be1000 rpm at 0.5 min, and are applicable to all sizes of the Unguatorcartridge line of containers with the herein described adapters.

Example 11

In this example, grinding of variable amounts of ingredient particleswas performed the herein described superimposed revolution and rotationmovements in a planetary mixer (Mazerustar kk-300ss, kk-400 or kk-1000)in presence of grinding media. The container was filled with grindingmedia and the ingredient particles. The dispersing time and thedispersing speed parameters were modified, and a dispersing assessmentwas made, as indicated in the following tables.

It is to be noted that this tables make reference to particle sizedistribution values such as D₁₀, D₅₀ and D₉₀. These are known manners torepresent particle size distribution. For example, D₉₀ signifies thepoint in the size distribution, up to and including which, 90% of thetotal volume of material in the sample is ‘contained’. For example, ifthe D₉₀ is 844 nm, this means that 90% of the sample has a size of 844nm or smaller.

TABLE 24 Standard NaCl particle size (LOT number 613788, NDC 0629)Surface Weighted Mean (μm) 248.715 Volume Weighted Mean (μm) 371.042 D₁₀(μm) 203.931 D₅₀ (μm) 354.291 D₉₀ (μm) 575.27

TABLE 25 Mazerustar KK-300SS - Constant time, variable G Force Test 1Test 2 Test 3 Test 4 NaCl 22.90 22.90 22.90 22.90 (grams) RPM 1100 13001600 1800 G Force 86 120 182 230 Time 60 60 60 60 (seconds) Surface17.011 10.850 N/A N/A Weighted Mean (μm) Volume 171.164 178.076 N/A N/AWeighted Mean (μm) D₁₀ (μm) 7.593 5.077 N/A N/A D₅₀ (μm) 44.899 31.239N/A N/A D₉₀ (μm) 725.785 826.723 N/A N/A Temperature 23.7 24.2 N/A N/ABefore (° C.) Temperature 43.3 52.0 N/A N/A After (° C.)

TABLE 26 Mazerustar KK-300SS - Variable time, constant G Force Test 1Test 6 Test 7 Test 8 Test 9 NaCl 22.90 22.90 22.90 22.90 22.90 (grams)RPM 1100 1100 1100 1100 1100 G Force 86 86 86 86 86 Time 60 90 120 180300 (seconds) Surface 17.011 7.933 6.284 4.956 4.56 Weighted Mean (μm)Volume 171.164 41.888 32.521 32.939 42.691 Weighted Mean (μm) D₁₀ (μm)7.593 3.992 3.190 2.292 2.012 D₅₀ (μm) 44.899 21.823 17.793 14.00212.835 D₉₀ (μm) 725.785 81.408 66.279 59.787 109.449 Temperature 23.722.1 24.3 23.5 26.0 Before (° C.) Temperature 43.3 54.1 58.8 46.7 64.7After (° C.)

TABLE 27 Mazerustar KK-400 - Constant time, variable G Force Test 1 Test2 Test 3 Test 4 NaCl 22.90 22.90 22.90 22.90 (grams) Revolution 5 6 7 8Setting # Rotation 5 6 7 8 Setting # RPM 804 935 1058 1218 G Force 98133 170 226 Time 60 60 60 60 (seconds) Surface 23.095 11.283 6.553 5.915Weighted Mean (μm) Volume 81.929 57.473 32.390 36.968 Weighted Mean (μm)D₁₀ (μm) 10.468 5.624 3.592 3.083 D₅₀ (μm) 64.028 31.677 17.864 15.731D₉₀ (μm) 181.26 107.833 68.490 83.828 Temperature 23.1 25.3 24.7 25.5Before (° C.) Temperature 34.1 47.3 63.7 78.4 After (° C.)

TABLE 28 Mazerustar 400 - Variable time, constant G Force Test 1 Test 6Test 7 Test 8 Test 9 NaCl 22.90 22.90 22.90 22.90 22.90 (grams)Revolution 5 5 5 5 5 Setting # Rotation 5 5 5 5 5 Setting # RPM 804 804804 804 804 G Force 98 98 98 98 98 Time 60 90 120 180 300 (seconds)Surface 23.095 11.527 8.580 5.84 4.82 Weighted Mean (μm) Volume 81.92944.4229 33.358 35.459 33.206 Weighted Mean (μm) D₁₀ (μm) 10.468 5.8894.613 2.864 2.278 D₅₀ (μm) 64.028 31.852 22.848 16.457 13.084 D₉₀ (μm)181.26 101.156 76.524 35.459 66.116 Temperature 23.1 26.6 24.9 26.9 26.3Before (° C.) Temperature 34.1 42.6 46.0 49.8 47.8 After (° C.)

Methods Reference Point

The Sodium Chloride (NaCl) powder was taken from the original packagedcontainer (LOT number: 613788) with a stainless steel laboratory spatulaand placed in an inert plastic container. The powder (NaCl) wastransferred to the laser diffraction particle sizer MasterSizer 2000®.The data was collected and the distribution was noted at D₁₀, D₅₀ andD₉₀. These measurements consist of the reference points for thefollowing milling experimental assay.

Mortar and Pestle

A two (2) decimal place balance was used to weight the Sodium Chloride(NaCl) powder (LOT #613788). During the weighing operations, a weighboat was placed on the balance and tared, two different amounts ofpowder (NaCl) were tested, i.e., 23 grams and 50 grams. Due to thevolume capacity difference of the planetary mixers tested, the weightsof 23 grams and 50 grams were selected. The results gathered from the 23grams trituration steps were used to compare with the KK-300SS andKK-400. The results gathered from the 50 grams trituration steps wereused to compare with the KK-1000. Once the desired mass of powder wasweighed, the powder (NaCl) was then transferred from the weigh boat to amortar and pestle. The triturating process began once the timer started.During testing, times of 60, 180 and 300 seconds were used. Also, two(2) different individuals performed the trituration process. Once thetime of a trituration nm had elapsed, the milled powder (NaCl) wastransferred from the mortar to an inert plastic container. A randomsample of 3 grams from the powder was placed in the laser diffractionparticle sizer MasterSizer 2000®. The data was collected and thedistribution was noted at D₁₀, D₅₀ and D₉₀. These measurements consistedof the reference points for the following milling experimental assay.

Mazerustar KK-300SS, KK-400 and KK-1000

A two (2) decimal place balance was used to weigh the Sodium Chloride(NaCl) powder (LOT #613788). During the weighing operations, a stainlesssteel liner was placed on the balance and tared. Two different amountsof powder (NaCl), 22.90 grams and 53.00 grams, which each occupied ¼ ofthe volume of their respective liners, were tested. The 22.90 gramsexperiments were tested on the Mazerustar KK-300SS and KK-400 units. The53.00 grams experiments were tested on the Mazerustar KK-1000 unit. Oncethe desired mass of powder was weighed, the spherical grinding media of8 mm diameter was added to the stainless steel container. For thisexperiment a total grinding media mass of 106.4 grams was used for theexperiments with 22.90 grams of powder, and a total grinding media massof 245.79 grams was used for the experiments with 53.00 grams of powder.

Mazerustar KK-300SS

Times of 60 seconds were used for increasing G Force and RPM. For theMazerustar KK-300SS: 86 G Force corresponds to 1100 RPM; 120 G Forcecorresponds to 1300 RPM; 182 G Force corresponds to 1600 RPM; 230 GForce corresponds to 1800 RPM.

Parameters of G Force of 86 (1100 RPM) were used for increasing the timeof milling in the Mazerustar. For the Mazerustar KK-300SS times of 60,90, 120, 180 and 300 seconds were used.

Mazerustar KK-400

Parameters of 60 seconds were used for increasing G Force and RPM. Forthe Mazerustar KK-400: 98 G Force corresponds to 804 RPM; 133 G Forcecorresponds to 935 RPM; 170 G Force corresponds to 1058 RPM; and 226 GForce corresponds to 1218 RPM.

Parameters of G Force of 98 (804 RPM) were used for increasing the timeof milling in the planetary mixer. For the Mazerustar KK-400 times of60, 90, 120, 180 and 300 seconds were used.

Mazerustar KK-1000

Parameters of 60 seconds were used for increasing G Force and RPM. Forthe Mazerustar KK-1000: 88 G Force corresponds to 590 RPM; 116 G Forcecorresponds to 680 RPM; 186 G Force corresponds to 960 RPM; 227 G Forcecorresponds to 960 RPM.

Parameters of G Force of 88 (590 RPM) were used for increasing the timeof milling in the planetary mixer. For the Mazerustar KK-1000 times of60, 90, 120, 180 and 300 seconds were used.

Once the time had elapsed, the milled powder was placed in an inertplastic container. A random sample of 3 grams from the powder was placedin the laser diffraction particle sizer MasterSizer 2000®. The data wascollected and the distribution was noted at D₁₀, D₅₀ and D₉₀. Thesemeasurements were the reference points for the following millingexperimental assay.

Clean up for the planetary mixer and for the mortar and pestle tookcomparatively the same period of time.

Observations

Constant G Force with Increased Time Duration

One can observe that compounding pharmaceutical ingredients using dueherein described superimposed revolution and rotation movements in thepresence of grinding media with a planetary mixer is very efficientcompared to the conventional method of the mortar and pestle.

The longer the duration, die finer the particles became. After 60seconds, the planetary mixer could bring die (D₁₀) within 10 μm. Themortar and pestle could barely reach (D₁₀) of 10 μm after 300 seconds.It is important to note the overall particle size for the (D₅₀) and(D₉₀). The planetary mixer could reduce the particle size within 60seconds for the overall particle size for the (D₅₀) and (D₉₀). Afterprocessing with the planetary mixer for a duration exceeding 180seconds, the powder reached a state whereby the fineness of the powderexhibited hygroscopic properties of clumping, creating larger particlesize.

Constant Time Duration with Increased G Force

One can observe that milling at higher G Force for the same durationdiminished the particle size in the planetary mixer. G Forces higherthan 170 demonstrated that particle size variance was very similar.

Temperature Gain for 60 Seconds at Different G Force

Increasing the G Force while maintaining a constant time milling time of60 seconds generated more friction between the stainless steel liner andthe zirconium coated balls, which in turn created a larger temperaturegain. This temperature gain stabilised once the 180 G Force mark waspassed.

Temperature Gain for Constant G Force at Different Time Duration

The temperature gain increased as the processing time increases. Thetemperature gain stabilised quickly for any value after the 90-secondmarks.

TABLE 29 Mazerustar KK-1000 - Constant time, variable G Force Test 1Test 2 Test 3 Test 4 NaCl 53.00 53.00 53.00 53.00 (grams) Revolution 5 68 9 Setting # Rotation 5 6 8 9 Setting # RPM 590 680 860 960 G Force 88116 186 227 Time 60 60 60 60 (seconds) Surface 190.024 20.891 5.5865.964 Weighted Mean (μm) Volume 375.514 80.659 28.893 40.497 WeightedMean (μm) D₁₀ (μm) 184.331 9.437 2.845 2.900 D₅₀ (μm) 361.686 60.39015.174 15.937 D₉₀ (μm) 602.621 182.817 63.131 97.955 Temperature 22.725.6 23.7 24.8 Before (° C.) Temperature 27.9 41.9 85.5 107.4 After (°C.)

TABLE 30 Mazerustar 1000 - Variable time, constant G Force Test 1 Test 6Test 7 Test 8 Test 9 NaCl (grams) 53.00 53.00 53.00 53.00 53.00 Rev # 55 5 5 5 Rot # 5 5 5 5 5 RPM 590 590 590 590 590 G Force 88 88 88 88 88Time (seconds) 60 90 120 180 300 Surface Weighted Mean 190.024 17.12810.585 6.498 10.365 (μm) Vol. Weighted Mean 375.514 69.509 40.890 33.68996.187 (μm) D₁₀ (μm) 184.331 7.750 5.386 3.295 5.12 D₅₀ (μm) 361.68645.419 28.919 19.327 32.163 D₉₀ (μm) 602.621 141.883 93.219 68.821127.26 Temperature Before 22.7 24.8 26.4 24.9 24.9 (° C.) TemperatureAfter 27.9 42.9 48.2 53.9 54.8 (° C.)

TABLE 31 Mortar & Pestle - Variable time & weight Test 1 Test 2 Test 3Test 4 Test 5 Test 6 User User 1 User 1 User 1 User 2 User 2 User 2 NaCl22.90 22.90 22.90 22.90 22.90 22.90 (grams) Time 60 180 300 60 180 300(seconds) D₁₀ (μm) 79.86 19.108 10.27 128.563 26.732 8.070 D₅₀ (μm)322.183 218.789 127.252 329.516 253.368 103.698 D₉₀ (μm) 564.429 459.647326.609 567.004 493.422 287.631 Temp. 25.6 26.3 26.8 N/A N/A N/A Before(° C.) Temp. 26.3 26.8 27.0 N/A N/A N/A After (° C.)

TABLE 32 Mortar & Pestle - Variable time & weight Test 7 Test 8 Test 9Test 10 Test 11 Test 12 User User 1 User 1 User 1 User 2 User 2 User 2NaCl 50.00 50.00 50.00 50.00 50.00 50.00 (grams) Time 60 180 300 60 180300 (seconds) D₁₀ (μm) 187.352 157.311 99.553 184.351 114.791 89.662 D₅₀(μm) 358.969 346.437 327.158 348.63 331.814 322.701 D₉₀ (μm) 593.531586.343 567.563 584.389 575.718 561.756 Temperature 25.1 24.7 25.4 N/AN/A N/A Before (° C.) Temperature 24.7 25.4 25.4 N/A N/A N/A After (°C.)

Example 12

In the following experiment, a compounding composition including 3 APIwas dispersed in an excipient was prepared according to the hereindescribed superimposed revolution and rotation movements, or using anElectric Mortar and Pestle (EMP) Mixer as control comparative mixingdevice. The characteristics of the resulting composition were assessed.Notably, this experiment demonstrated that the superimposed revolutionand rotation movements can be implemented independently of theprocessing capacity or planetary mixer model used.

Homogeneity was assessed by measuring the API potency with highperformance liquid chromatography (HPLC) at three layers of a givenmixing vessel (top, middle and bottom layers). The API potency wasreported in the form of a weight/weight concentration on triplicatebatches. In other words, the formulation for a given container andvolume size was repeated three (3) times in order to obtainstatistically significant data.

The assays were performed with different planetary mixer models, namelythe Mazerustar KK-300SS, KK-400W, and KK-1000W and an EMP Mixer.

Samples were prepared using six (6) different mixer/volumeconfigurations with a formula of Baclofen 2%, Cyclobenzaprine 6% andDiclofenac 10% in VersaPro™ Cream. Briefly, the baclofen andcyclobenzaprine hydrochloride were weighted into separate glass mortarand pestles. The baclofen and cyclobenzaprine hydrochloride weretriturated until a fine powder with no grittiness was formed. In a glassmortar and pestle the desired quantity of baclofen, cyclobenzaprinehydrochloride and diclofenac sodium were combined. Desired amounts ofethoxy diglycol and pentylene glycol were incorporated into the powderblend until the powder blend was levigated and a smooth paste wasachieved.

The dispersing container (Mazerustar or EMP jar) was filled with thedesired amount of Versapro Cream and placed into the respective device(planetary Mazerustar or EMP). The parameters for operating the deviceswere set, including revolution, rotation and time variables for theplanetary mixers.

The resulting 3 API formulation composition were separated in thecontainer into three layers, namely top (T), middle (M) and bottom (B)layers.

TABLE 33 List of Ingredients for 3-API Formulation grams or mL 1 2 3 KK-KK- KK- 4 5 6 300SS 400W 1000W EMP EMP EMP Ingredient (200 g) (300 g)(750 g) (200 g) (300 g) (750 g) NDC Lot Baclofen USP 4 6 15 Baclofen USP4 6 15 Baclofen USP Cyclobenzaprine 12 18 45 Cyclobenzaprine 12 18 45Cyclobenzaprine Hydrochloride Hydrochloride Hydrochloride USP USP USPDiclofenac 20 30 75 Diclofenac 20 30 75 Diclofenac Sodium USP Sodium USPSodium USP (Micronized) (Micronized) (Micronized) Ethoxy Diglycol 9 13.536 Ethoxy Diglycol 9 13.5 36 Ethoxy Diglycol Pentylene Glycol 8 12 30Pentylene Glycol 8 12 30 Pentylene Glycol VersaPro Cream 147 220.5 549VersaPro Cream 147 220.5 549 VersaPro Cream Base Base Base

The superimposed revolution and rotation movement parameters in theplanetary mixer were (samples 1-3):

-   -   1. Mazerustar KK-300SS: 2000 RPM (revolution)/800 RPM (rotation)        for 30 sec (standard jar) [which provides a G force of 284 g]    -   2. Mazerustar KK-400W: 1340 RPM (revolution)/1340 RPM (rotation)        for 70 sec [which provides a G force of 273 g]    -   3. Mazerustar KK-1000W: 960 RPM (revolution)/950 RPM (rotation)        for 130 sec [which provides a G force of 227 g]

The EMF parameters were (samples 4-6):

-   -   4. EMP 200 mL Jar: Lift Engine Step 01, Mix Engine Step 06 for        120 sec    -   5. EMP 300 ml. Jar: Lift Engine Step 01, Mix Engine Step 06 for        120 sec    -   6. EMP 1 L Jar Lift Engine Step 01, Mix Engine Step 06 for 180        sec

Each of the resulting composition was then separated in top, middle andbottom layers and the concentration of each of the 3 API in each layerwas measured with HPLC. The average concentration ([ ]), the standarddeviation (SD) and the relative standard deviation (% RSD) werecalculated for each API. The results are shown in the following Tables:

TABLE 34 Results for a composition including 3 API dispersed inMazerustar KK-300SS Layer Formu- (top, lation Sample middle, BaclofenCyclobenzaprine Diclofenac # # bottom) (w/w) (w/w) (w/w) 1 1 Top 2.0456.144 10.045 2 Middle 2.019 6.070 9.925 3 Bottom 2.070 6.175 10.114 2 4Top 1.992 6.129 9.970 5 Middle 2.085 6.251 10.156 6 Bottom 2.032 6.27010.191 3 7 Top 2.071 6.334 10.319 8 Middle 2.070 6.311 10.265 9 Bottom2.116 6.421 10.456

TABLE 35 Results for a composition including 3 API dispersed inMazerustar KK-400W Layer Formu- (top, lation Sample middle, BaclofenCyclobenzaprine Diclofenac # # bottom) (w/w) (w/w) (w/w) 4 10 Top 2.0896.332 10.334 11 Middle 2.113 6.345 10.375 12 Bottom 2.127 6.316 10.352 513 Top 2.069 6.340 10.292 14 Middle 2.090 6.426 10.486 15 Bottom 2.0516.397 10.438 6 16 Top 2.067 6.321 10.306 17 Middle 2.094 6.312 10.3 18Bottom 2.081 6.394 10.41

TABLE 36 Results for a composition including 3 API dispersed inMazerustar KK-1000W Layer Formu- (top, lation Sample middle, BaclofenCyclobenzaprine Diclofenac # # bottom) (w/w) (w/w) (w/w) 7 19 Top 2.0856.432 10.556 20 Middle 2.068 6.435 10.535 21 Bottom 2.039 6.295 10.32 822 Top 2.105 6.426 10.374 23 Middle 2.106 6.427 10.389 24 Bottom 2.0866.46 10.418 9 25 Top 2.130 6.369 10.382 26 Middle 2.108 6.224 10.179 27Bottom 2.107 6.294 10.28

TABLE 37 Results for a composition including 3 API dispersed in EMP 200mL Jar Layer Formu- (top, lation Sample middle, Baclofen CyclobenzaprineDiclofenac # # bottom) (w/w) (w/w) (w/w) 10 28 Top 2.165 6.475 10.612 29Middle 2.021 6.089 9.985 30 Bottom 2.024 6.11 10.021 11 31 Top 2.1336.44 10.536 32 Middle 2.12 6.288 10.285 33 Bottom 2.05 6.212 10.169 1234 Top 2.209 6.457 10.565 35 Middle 2.074 6.182 10.136 36 Bottom 2.1136.279 10.288

TABLE 38 Results for a composition including 3 API dispersed in EMP 300ml Jar Layer Formu- (top, lation Sample middle, Baclofen CyclobenzaprineDiclofenac # # bottom) (w/w) (w/w) (w/w) 13 37 Top 2.235 6.674 10.935 38Middle 2.082 6.272 10.295 39 Bottom 2.208 6.48 10.604 14 40 Top 2.1856.557 10.752 41 Middle 2.087 6.205 10.15 42 Bottom 1.998 6.047 9.908 1543 Top 2.23 6.743 11.035 44 Middle 2.089 6.228 10.205 45 Bottom 2.0446.216 10.193

TABLE 39 Results for a composition including 3 API dispersed in EMP 1 LJar Layer Formu- (top, lation Sample middle, Baclofen CyclobenzaprineDiclofenac # # bottom) (w/w) (w/w) (w/w) 16 46 Top 2.113 6.376 10.454 47Middle 2.073 6.097 10.003 48 Bottom 2.101 6.147 10.093 17 49 Top 2.0316.294 10.301 50 Middle 2.094 6.488 10.558 51 Bottom 1.987 6.182 10.02118 52 Top 2.098 6.396 10.284 53 Middle 2.154 6.506 10.486 54 Bottom2.088 6.182 9.932

TABLE 40 % RSD Results for the compositions of Table 34 to 39 Formu-lation Baclofen, 2% Cyclobenzaprine, 6% Diclofenac, 10% # % RSD 1 1.2%0.9% 1.0% 2 2.3% 1.2% 1.2% 3 1.3% 0.9% 1.0% 4 0.9% 0.2% 0.2% 5 0.9% 0.7%1.0% 6 0.6% 0.7% 0.6% 7 1.1% 1.3% 1.2% 8 0.5% 0.3% 0.2% 9 0.6% 1.2% 1.0%10 4.0% 3.5% 3.4% 11 2.1% 1.8% 1.8% 12 3.3% 2.2% 2.1% 13 3.8% 3.1% 3.0%14 4.5% 4.2% 4.2% 15 4.6% 4.7% 4.6% 16 1.0% 2.4% 2.3% 17 2.6% 2.4% 2.6%18 1.7% 2.6% 2.7%

Example 13

In the following experiment, a compounding composition including 2 APIwas dispersed in an excipient was prepared according to the hereindescribed superimposed revolution and rotation movements, or using anElectric Mortar and Pestle (EMP) Mixer as control comparative mixingdevice, lire characteristics of the resulting composition were assessed.Notably, this experiment demonstrated that the superimposed revolutionand rotation movements can be implemented independently of theprocessing capacity or planetary mixer model used.

Homogeneity was assessed as in Example 12. The dispersing processes wereperformed with the same devices as in Example 12.

Samples were prepared using six (6) different mixer/volumeconfigurations with a formula of Estradiol 0.05% and Estriol 0.2% inVersaPro Cream. Briefly, the estradiol and estriol were weighted intoseparate plastic weigh boats. A 3 decimal place balance was used toprepare the formulation. Desired amounts of propylene glycol wereincorporated into the powder blend until the powder blend was levigatedand a smooth homogeneous liquid. The dispersing container (Mazerustar orEMP jar) was filled with the desired amount of Versapro Cream and placedinto the respective device (planetary Mazerustar or EMP). The parametersfor operating the devices were set, including revolution, rotation andtime variables for the planetary mixers.

The resulting 2 API formulation composition were separated in thecontainer into three layers, namely top (T), middle (M) and bottom (B)layers.

TABLE 41 List of Ingredients for 2-API Formulation grams or mL 1 2 3 KK-KK- KK- 4 5 6 300SS 400 1000 EMP EMP EMP Ingredient (200 g) (300 g) (750g) (200 g) (300 g) (750 g) NDC Lot Estradiol, USP 0.1 0.15 0.375 0.10.15 0.375 0869 614901/B (Micronized) Estriol USP 0.4 0.6 1.5 0.4 0.61.5 0732 615107/B (Micronized) Propylene 1 1.5 3.75 1 1.5 3.75 0510605764/C Glycol VersaPro 198.5 297.75 744.375 198.5 297.75 744.375 2529611448 Cream Base

The superimposed revolution and rotation movement parameters in theplanetary mixer (samples 1-3) and the EMF parameters (samples 4-6) werethe same as in Example 12.

Each of the resulting composition was then separated and analyzed as inExample 12. The results are shown in the following Tables:

TABLE 42 Results for a composition including 2 API dispersed in KK-300SSLayer Formu- (top, lation Sample middle, Estriol Estradiol # # bottom)(w/w) (w/w) 19 55 Top 0.181 0.055 56 Middle 0.179 0.055 57 Bottom 0.1830.054 20 58 Top 0.211 0.046 59 Middle 0.204 0.044 60 Bottom 0.208 0.04521 61 Top 0.199 0.048 62 Middle 0.198 0.047 63 Bottom 0.196 0.047

TABLE 43 Results for a composition including 2 API dispersed inMazerustar KK-400W Layer Formu- (top, lation Sample middle, EstriolEstradiol # # bottom) (w/w) (w/w) 22 64 Top 0.195 0.049 65 Middle 0.1940.048 66 Bottom 0.194 0.049 23 67 Top 0.201 0.048 68 Middle 0.201 0.04869 Bottom 0.201 0.048 24 70 Top 0.18 0.05 71 Middle 0.181 0.051 72Bottom 0.181 0.05

TABLE 44 Results for a composition including 2 API dispersed inMazerustar KK-1000W Layer Formu- (top, lation Sample middle, EstriolEstradiol # # bottom) (w/w) (w/w) 25 73 Top 0.201 0.05 74 Middle 0.2030.051 75 Bottom 0.202 0.05 26 76 Top 0.198 0.037 77 Middle 0.198 0.03778 Bottom 0.197 0.037 27 79 Top 0.203 0.051 80 Middle 0.201 0.051 81Bottom 0.201 0.051

TABLE 45 Results for a composition including 2 API dispersed in EMP 200mL Jar Layer Formu- (top, lation Sample middle, Estriol Estradiol # #bottom) (w/w) (w/w) 28 82 Top 0.236 0.058 83 Middle 0.19 0.047 84 Bottom0.169 0.041 29 85 Top 0.247 0.064 86 Middle 0.164 0.043 87 Bottom 0.1320.034 30 88 Top 0.303 0.07 89 Middle 0.179 0.041 90 Bottom 0.141 0.033

TABLE 46 Results for a composition including 2 API dispersed in EMP 300mL Jar Layer Formu- (top, lation Sample middle, Estriol Estradiol # #bottom) (w/w) (w/w) 31 91 Top 0.213 0.055 92 Middle 0.207 0.053 93Bottom 0.177 0.045 32 94 Top 0.207 0.053 95 Middle 0.168 0.043 96 Bottom0.17 0.044 33 97 Top 0.204 0.056 98 Middle 0.203 0.055 99 Bottom 0.1930.053

TABLE 47 Results for a composition including 2 API dispersed in EMP 1 LJar Layer Formu- (top, lation Sample middle, Estriol Estradiol # #bottom) (w/w) (w/w) 34 100 Top 0.183 0.044 101 Middle 0.184 0.044 102Bottom 0.178 0.043 35 103 Top 0.15 0.038 104 Middle 0.16 0.041 105Bottom 0.16 0.041 36 106 Top 0.183 0.043 107 Middle 0.166 0.039 108Bottom 0.174 0.041

TABLE 48 % RSD Results for the compositions of Tables 42 to 47 EstriolEstradiol Formulation % RSD 19 1.1% 1.1% 20 1.7% 2.2% 21 0.8% 0.0% 220.3% 1.2% 23 0.0% 0.0% 24 0.3% 1.1% 25 0.5% 1.1% 26 0.3% 0.0% 27 0.6%0.0% 28 17.3% 17.7% 29 32.8% 32.8% 30 40.8% 40.6% 31 9.7% 10.4% 32 12.1%11.8% 33 3.0% 2.8% 34 1.8% 1.3% 35 3.7% 4.3% 36 4.9% 4.9%

Other examples of implementations will become apparent to the reader inview of the teachings of the present description and as such, will notbe further described here.

Note that tides or subtitles may be used throughout the presentdisclosure for convenience of a reader, but in no way these should limitthe scope of the invention. Moreover, certain theories may be proposedand disclosed herein; however, in no way they, whether they are right orwrong, should limit the scope of the invention so long as the inventionis practiced according to the present disclosure without regard for anyparticular theory or scheme of action.

All references cited throughout the specification are herebyincorporated by reference in their entirety for all purposes.

It will be understood by those of skill in the art that throughout thepresent specification, the term “a” used before a term encompassesembodiments containing one or more to what the term refers. It will alsobe understood by those of skill in the art that throughout the presentspecification, the term “comprising”, which is synonymous with“including,” “containing,” or “characterized by,” is inclusive oropen-ended and does not exclude additional, un-recited elements ormethod steps.

Unless otherwise defined, all technical and scientific terms used hereinhave the same meaning as commonly understood by one of ordinary skill inthe art to which this disclosure pertains. In the case of conflict, thepresent document, including definitions will control.

As used m the present disclosure, the terms “around”, “about” or“approximately” shall generally mean within the error margin generallyaccepted in the art Hence, numerical quantities given herein generallyinclude such error margin such that the terms “around”, “about” or“approximately” can be inferred if not expressly stated.

In the present disclosure, each of the variously stated ranges isintended to be continuous so as to include each numerical parameterbetween the stated minimum and maximum value of each range. For Example,a range of about 1 to about 4 includes: about 1, 1, about 2, 2, about 3,3, about 4, and 4.

Although various embodiments of the disclosure have been described andillustrated, it will be apparent to those skilled in the art in light ofthe present description that numerous modifications and variations canbe made. The scope of the invention is defined more particularly in theappended claims.

We claim:
 1. A container assembly for use in a planetary mixer, comprising a jar with an inner wall, an adapter in contact with the inner wall of the jar, a metered-dosage dispenser having a tubular body, and a lid attachable to an rim of the jar, wherein the adapter is configured to clamp to the metered-dosage dispenser, the adapter being further configured to keep the metered-dosage dispenser away from the inner wall of the jar, wherein at least a portion of the metered-dosage dispenser is configured to allow visibility of at least some contents inside the body of the metered-dosage dispenser from outside the body of the metered-dosage dispenser, wherein the adapter is free of material along a longitudinal axis of the jar and has a plurality of apertures surrounding the longitudinal axis of the jar and wherein the body of the metered-dosage dispenser has a height-to-base ratio (HBR) between 0.75 and 1.5 at half volume and has a greater HBR than the jar for the same total volume.
 2. The container assembly defined in claim 1, wherein the metered-dosage dispenser comprises a cap.
 3. The container assembly defined in claim 2, wherein there is a gap between the rim of the jar and the cap of the metered-dosage dispenser.
 4. The container assembly defined in claim 3, wherein at least a portion of the cap of metered-dosage dispenser is closet to the rim of the jar than a portion of the body of the metered-dosage dispenser.
 5. The container assembly defined in claim 4, wherein the body of the metered-dosage is elongated along an axis of the body and wherein the cap that is wider than tire body of the metered-dosage dispenser when measured transverse to the axis of the body.
 6. The container assembly defined in claim 1, wherein the jar has a bottom wall and wherein the adapter is in contact with the bottom wall.
 7. The container assembly defined in claim 1, wherein the lid is a screw-on lid.
 8. The container assembly defined in claim 1, wherein the jar is cylindrical.
 9. The container assembly defined in claim 1, wherein die adapter extends along the longitudinal axis of the jar to a greater extent than the adapter.
 10. The container assembly defined in claim 1, wherein the adapter includes a circumferential band having a thickness along the longitudinal axis of die jar between the bottom wall of the jar and a part of the dispenser closest to the bottom wall of the jar.
 11. The container assembly defined in claim 1, wherein the dispenser crosses the longitudinal axis of the jar.
 12. The container assembly defined in claim 11, wherein the dispenser extends over more than half the diameter of the jar.
 13. The container assembly defined in claim 1, wherein the dispenser is clamped to the adapter in at least two places.
 14. The container assembly defined in claim 2, wherein the cap of the dispenser is circular.
 15. The container assembly defined in claim 1, wherein the jar is made of plastic.
 16. A container assembly for use in a planetary mixer, comprising a cylindrical plastic jar with an inner wall and a bottom wall, a screw-on lid attachable to an rim of the jar, an adapter in contact with the inner and bottom walls of the jar, a metered-dosage dispenser having a tubular body and a circular cap, wherein the adapter is configured to secure to the metered-dosage dispenser in at least two places, the adapter being further configured to keep the metered-dosage dispenser away from the inner wall of the jar, wherein at least a portion of the metered-dosage dispenser is configured to allow visibility of at least some contents inside the body of the metered-dosage dispenser from outside the body of the metered-dosage dispenser, wherein the adapter is free of material along a longitudinal axis of the jar and has a plurality of apertures surrounding the longitudinal axis of the jar and wherein the body of the metered-dosage dispenser has a height-to-base ratio (HBR) between 0.75 and 1.5 at half volume and has a greater HBR than the jar for the same total volume, wherein there is a gap between the rim of the jar and the cap of the metered-dosage dispenser, wherein at least a portion of the cap of metered-dosage dispenser is closer to the rim of the jar than a portion of the body of the metered-dosage dispenser, wherein the body of the metered-dosage is elongated along an axis of the body and wherein the cap of the metered-dosage dispenser is wider than the body of the metered-dosage dispenser when measured transverse to the axis of the body, wherein the adapter extends along the longitudinal axis of the jar to a greater extent than the adapter, wherein the adapter includes a circumferential band having a thickness along the longitudinal axis of the jar between the bottom wall of the jar and a part of the dispenser closest to the bottom wall of the jar, wherein the dispenser crosses the longitudinal axis of the jar, wherein the dispenser extends over mote than half the diameter of the jar.
 17. The container assembly defined in claim 16, used in a pharmacy setting. 